Receptors, Aryl Hydrocarbon: Cytoplasmic proteins that bind certain aryl hydrocarbons, translocate to the nucleus, and activate transcription of particular DNA segments. AH receptors are identified by their high-affinity binding to several carcinogenic or teratogenic environmental chemicals including polycyclic aromatic hydrocarbons found in cigarette smoke and smog, heterocyclic amines found in cooked foods, and halogenated hydrocarbons including dioxins and polychlorinated biphenyls. No endogenous ligand has been identified, but an unknown natural messenger with a role in cell differentiation and development is suspected.Aryl Hydrocarbon Hydroxylases: A large group of cytochrome P-450 (heme-thiolate) monooxygenases that complex with NAD(P)H-FLAVIN OXIDOREDUCTASE in numerous mixed-function oxidations of aromatic compounds. They catalyze hydroxylation of a broad spectrum of substrates and are important in the metabolism of steroids, drugs, and toxins such as PHENOBARBITAL, carcinogens, and insecticides.HydrocarbonsTetrachlorodibenzodioxin: A chemical by-product that results from burning or incinerating chlorinated industrial chemicals and other hydrocarbons. This compound is considered an environmental toxin, and may pose reproductive, as well as, other health risks for animals and humans.Aryl Hydrocarbon Receptor Nuclear Translocator: Aryl hydrocarbon receptor nuclear translocator is a basic HELIX-LOOP-HELIX MOTIF containing protein that forms a complex with DIOXIN RECEPTOR. The complex binds xenobiotic regulatory elements and activates transcription of a variety of genes including UDP GLUCURONOSYLTRANSFERASE. AhR nuclear translocator is also a subunit of HYPOXIA-INDUCIBLE FACTOR 1.Cytochrome P-450 CYP1A1: A liver microsomal cytochrome P-450 monooxygenase capable of biotransforming xenobiotics such as polycyclic hydrocarbons and halogenated aromatic hydrocarbons into carcinogenic or mutagenic compounds. They have been found in mammals and fish. This enzyme, encoded by CYP1A1 gene, can be measured by using ethoxyresorufin as a substrate for the ethoxyresorufin O-deethylase activity.Polycyclic Hydrocarbons, Aromatic: A major group of unsaturated cyclic hydrocarbons containing two or more rings. The vast number of compounds of this important group, derived chiefly from petroleum and coal tar, are rather highly reactive and chemically versatile. The name is due to the strong and not unpleasant odor characteristic of most substances of this nature. (From Hawley's Condensed Chemical Dictionary, 12th ed, p96)Procollagen-Proline Dioxygenase: A mixed-function oxygenase that catalyzes the hydroxylation of a prolyl-glycyl containing peptide, usually in PROTOCOLLAGEN, to a hydroxyprolylglycyl-containing-peptide. The enzyme utilizes molecular OXYGEN with a concomitant oxidative decarboxylation of 2-oxoglutarate to SUCCINATE. The enzyme occurs as a tetramer of two alpha and two beta subunits. The beta subunit of procollagen-proline dioxygenase is identical to the enzyme PROTEIN DISULFIDE-ISOMERASES.Dioxins: Chlorinated hydrocarbons containing heteroatoms that are present as contaminants of herbicides. Dioxins are carcinogenic, teratogenic, and mutagenic. They have been banned from use by the FDA.Mixed Function Oxygenases: Widely distributed enzymes that carry out oxidation-reduction reactions in which one atom of the oxygen molecule is incorporated into the organic substrate; the other oxygen atom is reduced and combined with hydrogen ions to form water. They are also known as monooxygenases or hydroxylases. These reactions require two substrates as reductants for each of the two oxygen atoms. There are different classes of monooxygenases depending on the type of hydrogen-providing cosubstrate (COENZYMES) required in the mixed-function oxidation.Benzo(a)pyrene: A potent mutagen and carcinogen. It is a public health concern because of its possible effects on industrial workers, as an environmental pollutant, an as a component of tobacco smoke.Methylcholanthrene: A carcinogen that is often used in experimental cancer studies.Hydrocarbons, Aromatic: Organic compounds containing carbon and hydrogen in the form of an unsaturated, usually hexagonal ring structure. The compounds can be single ring, or double, triple, or multiple fused rings.Benz(a)Anthracenes: Four fused benzyl rings with three linear and one angular, that can be viewed as a benzyl-phenanthrenes. Compare with NAPHTHACENES which are four linear rings.Prolyl Hydroxylases: Enzymes that specifically hydroxylate PROLINE residues on proteins.Hypoxia-Inducible Factor-Proline Dioxygenases: Dioxygenase enzymes that specifically hydroxylate a PROLINE residue on the HYPOXIA-INDUCIBLE FACTOR 1, ALPHA SUBUNIT. They are OXYGEN-dependent enzymes that play an important role in mediating cellular adaptive responses to HYPOXIA.Steroid Hydroxylases: Cytochrome P-450 monooxygenases (MIXED FUNCTION OXYGENASES) that are important in steroid biosynthesis and metabolism.Environmental Pollutants: Substances or energies, for example heat or light, which when introduced into the air, water, or land threaten life or health of individuals or ECOSYSTEMS.Enzyme Induction: An increase in the rate of synthesis of an enzyme due to the presence of an inducer which acts to derepress the gene responsible for enzyme synthesis.Polycyclic Compounds: Compounds consisting of two or more fused ring structures.Cytochrome P-450 Enzyme System: A superfamily of hundreds of closely related HEMEPROTEINS found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (MIXED FUNCTION OXYGENASES). In animals, these P-450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (BIOTRANSFORMATION). They are classified, according to their sequence similarities rather than functions, into CYP gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the CYP1, CYP2, and CYP3 gene families are responsible for most drug metabolism.Hydroxylation: Placing of a hydroxyl group on a compound in a position where one did not exist before. (Stedman, 26th ed)beta-Naphthoflavone: A polyaromatic hydrocarbon inducer of P4501A1 and P4501A2 cytochromes. (Proc Soc Exp Biol Med 1994 Dec:207(3):302-308)Benzoflavones: Organic compounds containing a BENZENE ring attached to a flavone group. Some of these are potent arylhydrocarbon hydroxylase inhibitors. They may also inhibit the binding of NUCLEIC ACIDS to BENZOPYRENES and related compounds. The designation includes all isomers; the 7,8-isomer is most frequently encountered.Benzopyrenes: A class of chemicals that contain an anthracene ring with a naphthalene ring attached to it.Hypoxia-Inducible Factor 1, alpha Subunit: Hypoxia-inducible factor 1, alpha subunit is a basic helix-loop-helix transcription factor that is regulated by OXYGEN availability and is targeted for degradation by VHL TUMOR SUPPRESSOR PROTEIN.Hydrocarbons, HalogenatedBenzopyrene Hydroxylase: A drug-metabolizing, cytochrome P-448 (P-450) enzyme which catalyzes the hydroxylation of benzopyrene to 3-hydroxybenzopyrene in the presence of reduced flavoprotein and molecular oxygen. Also acts on certain anthracene derivatives. An aspect of EC 1.14.14.1.Alkanes: The generic name for the group of aliphatic hydrocarbons Cn-H2n+2. They are denoted by the suffix -ane. (Grant & Hackh's Chemical Dictionary, 5th ed)Polychlorinated Biphenyls: Industrial products consisting of a mixture of chlorinated biphenyl congeners and isomers. These compounds are highly lipophilic and tend to accumulate in fat stores of animals. Many of these compounds are considered toxic and potential environmental pollutants.Basic Helix-Loop-Helix Transcription Factors: A family of DNA-binding transcription factors that contain a basic HELIX-LOOP-HELIX MOTIF.Hydrocarbons, Chlorinated: Hydrocarbon compounds with one or more of the hydrogens replaced by CHLORINE.Xenobiotics: Chemical substances that are foreign to the biological system. They include naturally occurring compounds, drugs, environmental agents, carcinogens, insecticides, etc.Teratogens: An agent that causes the production of physical defects in the developing embryo.Hypoxia-Inducible Factor 1: A basic helix-loop-helix transcription factor that plays a role in APOPTOSIS. It is composed of two subunits: ARYL HYDROCARBON RECEPTOR NUCLEAR TRANSLOCATOR and HYPOXIA-INDUCIBLE FACTOR 1, ALPHA SUBUNIT.Cytochrome P-450 CYP1A2: A cytochrome P450 enzyme subtype that has specificity for relatively planar heteroaromatic small molecules, such as CAFFEINE and ACETAMINOPHEN.Alkane 1-Monooxygenase: A P450 oxidoreductase that catalyzes the hydroxylation of the terminal carbon of linear hydrocarbons such as octane and FATTY ACIDS in the omega position. The enzyme may also play a role in the oxidation of a variety of structurally unrelated compounds such as XENOBIOTICS, and STEROIDS.RNA, Messenger: RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm.Ketoglutaric Acids: A family of compounds containing an oxo group with the general structure of 1,5-pentanedioic acid. (From Lehninger, Principles of Biochemistry, 1982, p442)Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase: A mixed-function oxygenase that catalyzes the hydroxylation of peptidyllysine, usually in protocollagen, to peptidylhydroxylysine. The enzyme utilizes molecular oxygen with concomitant oxidative decarboxylation of the cosubstrate 2-oxoglutarate to succinate. EC 1.14.11.4.Aldehyde Oxidase: An aldehyde oxidoreductase expressed predominantly in the LIVER; LUNGS; and KIDNEY. It catalyzes the oxidation of a variety of organic aldehydes and N-heterocyclic compounds to CARBOXYLIC ACIDS, and also oxidizes quinoline and pyridine derivatives. The enzyme utilizes molybdenum cofactor and FAD as cofactors.Dioxygenases: Non-heme iron-containing enzymes that incorporate two atoms of OXYGEN into the substrate. They are important in biosynthesis of FLAVONOIDS; GIBBERELLINS; and HYOSCYAMINE; and for degradation of AROMATIC HYDROCARBONS.Liver: A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances.Molecular Sequence Data: Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.Carcinogens: Substances that increase the risk of NEOPLASMS in humans or animals. Both genotoxic chemicals, which affect DNA directly, and nongenotoxic chemicals, which induce neoplasms by other mechanism, are included.Phenylalanine Hydroxylase: An enzyme of the oxidoreductase class that catalyzes the formation of L-TYROSINE, dihydrobiopterin, and water from L-PHENYLALANINE, tetrahydrobiopterin, and oxygen. Deficiency of this enzyme may cause PHENYLKETONURIAS and PHENYLKETONURIA, MATERNAL. EC 1.14.16.1.Gene Expression Regulation, Enzymologic: Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control of gene action in enzyme synthesis.Ligands: A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. Ligands are also molecules that donate or accept a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex. (From Dorland, 27th ed)Cholestanetriol 26-Monooxygenase: An NAPH-dependent cytochrome P450 enzyme that catalyzes the oxidation of the side chain of sterol intermediates such as the 27-hydroxylation of 5-beta-cholestane-3-alpha,7-alpha,12-alpha-triol.Mice, Inbred C57BLCell Line, Tumor: A cell line derived from cultured tumor cells.Chloracne: ACNE-like skin eruptions caused by exposure to CHLORINE-containing compounds. Exposure can be by inhalation, ingestion, or through the skin. Chloracne is often seen in people who have occupational contact with chlorinated pesticides, wood preservatives, and sealants.Biodegradation, Environmental: Elimination of ENVIRONMENTAL POLLUTANTS; PESTICIDES and other waste using living organisms, usually involving intervention of environmental or sanitation engineers.Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process.Petroleum: Naturally occurring complex liquid hydrocarbons which, after distillation, yield combustible fuels, petrochemicals, and lubricants.Microsomes, Liver: Closed vesicles of fragmented endoplasmic reticulum created when liver cells or tissue are disrupted by homogenization. They may be smooth or rough.Pyrenes: A group of condensed ring hydrocarbons.Oxygenases: Oxidases that specifically introduce DIOXYGEN-derived oxygen atoms into a variety of organic molecules.Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION.Soil Pollutants: Substances which pollute the soil. Use for soil pollutants in general or for which there is no specific heading.9,10-Dimethyl-1,2-benzanthracene: 7,12-Dimethylbenzanthracene. Polycyclic aromatic hydrocarbon found in tobacco smoke that is a potent carcinogen.Steroids, Fluorinated: Steroids which are substituted with one or more fluorine atoms in any position.Gene Expression Regulation: Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control (induction or repression) of gene action at the level of transcription or translation.Cell Hypoxia: A condition of decreased oxygen content at the cellular level.Tryptophan Hydroxylase: An enzyme that catalyzes the hydroxylation of TRYPTOPHAN to 5-HYDROXYTRYPTOPHAN in the presence of NADPH and molecular oxygen. It is important in the biosynthesis of SEROTONIN.Transcription, Genetic: The biosynthesis of RNA carried out on a template of DNA. The biosynthesis of DNA from an RNA template is called REVERSE TRANSCRIPTION.Xanthine Dehydrogenase: An enzyme that catalyzes the oxidation of XANTHINE in the presence of NAD+ to form URIC ACID and NADH. It acts also on a variety of other purines and aldehydes.Benzofurans: Compounds that contain a BENZENE ring fused to a furan ring.Cell Line: Established cell cultures that have the potential to propagate indefinitely.Molybdenum: A metallic element with the atomic symbol Mo, atomic number 42, and atomic weight 95.94. It is an essential trace element, being a component of the enzymes xanthine oxidase, aldehyde oxidase, and nitrate reductase. (From Dorland, 27th ed)Oxygen: An element with atomic symbol O, atomic number 8, and atomic weight [15.99903; 15.99977]. It is the most abundant element on earth and essential for respiration.Base Sequence: The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence.Jaw Abnormalities: Congenital absence of or defects in structures of the jaw.Fundulidae: Family of small, surface-dwelling fish that inhabit fresh and brackish waters, and coastal marine areas.Water Pollutants, Chemical: Chemical compounds which pollute the water of rivers, streams, lakes, the sea, reservoirs, or other bodies of water.Signal Transduction: The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway.DNA Adducts: The products of chemical reactions that result in the addition of extraneous chemical groups to DNA.Cells, Cultured: Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.Reverse Transcriptase Polymerase Chain Reaction: A variation of the PCR technique in which cDNA is made from RNA via reverse transcription. The resultant cDNA is then amplified using standard PCR protocols.Anoxia: Relatively complete absence of oxygen in one or more tissues.Protein Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments.7-Alkoxycoumarin O-Dealkylase: A drug-metabolizing enzyme found in the hepatic, placental and intestinal microsomes that metabolizes 7-alkoxycoumarin to 7-hydroxycoumarin. The enzyme is cytochrome P-450- dependent.Carcinogens, Environmental: Carcinogenic substances that are found in the environment.Molecular Structure: The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds.DNA-Binding Proteins: Proteins which bind to DNA. The family includes proteins which bind to both double- and single-stranded DNA and also includes specific DNA binding proteins in serum which can be used as markers for malignant diseases.Methylococcus: A genus of gram-negative, aerobic, spherical cells usually occurring in pairs. The resting stage is considered a cyst. (From Bergey's Manual of Determinative Bacteriology, 9th ed)Dose-Response Relationship, Drug: The relationship between the dose of an administered drug and the response of the organism to the drug.Kinetics: The rate dynamics in chemical or physical systems.Palladium: A chemical element having an atomic weight of 106.4, atomic number of 46, and the symbol Pd. It is a white, ductile metal resembling platinum, and following it in abundance and importance of applications. It is used in dentistry in the form of gold, silver, and copper alloys.HSP90 Heat-Shock Proteins: A class of MOLECULAR CHAPERONES whose members act in the mechanism of SIGNAL TRANSDUCTION by STEROID RECEPTORS.Steroids, Chlorinated: Steroids which are substituted with one or more chlorine atoms in any position.Catalysis: The facilitation of a chemical reaction by material (catalyst) that is not consumed by the reaction.Helix-Loop-Helix Motifs: Recurring supersecondary structures characterized by 20 amino acids folding into two alpha helices connected by a non-helical "loop" segment. They are found in many sequence-specific DNA-BINDING PROTEINS and in CALCIUM-BINDING PROTEINS.Amino Acids, DicarboxylicVon Hippel-Lindau Tumor Suppressor Protein: A ubiquitin-protein ligase that mediates OXYGEN-dependent polyubiquitination of HYPOXIA-INDUCIBLE FACTOR 1, ALPHA SUBUNIT. It is inactivated in VON HIPPEL-LINDAU SYNDROME.Metabolic Detoxication, Drug: Reduction of pharmacologic activity or toxicity of a drug or other foreign substance by a living system, usually by enzymatic action. It includes those metabolic transformations that make the substance more soluble for faster renal excretion.Flavonoids: A group of phenyl benzopyrans named for having structures like FLAVONES.Binding Sites: The parts of a macromolecule that directly participate in its specific combination with another molecule.Microsomes: Artifactual vesicles formed from the endoplasmic reticulum when cells are disrupted. They are isolated by differential centrifugation and are composed of three structural features: rough vesicles, smooth vesicles, and ribosomes. Numerous enzyme activities are associated with the microsomal fraction. (Glick, Glossary of Biochemistry and Molecular Biology, 1990; from Rieger et al., Glossary of Genetics: Classical and Molecular, 5th ed)Mice, Knockout: Strains of mice in which certain GENES of their GENOMES have been disrupted, or "knocked-out". To produce knockouts, using RECOMBINANT DNA technology, the normal DNA sequence of the gene being studied is altered to prevent synthesis of a normal gene product. Cloned cells in which this DNA alteration is successful are then injected into mouse EMBRYOS to produce chimeric mice. The chimeric mice are then bred to yield a strain in which all the cells of the mouse contain the disrupted gene. Knockout mice are used as EXPERIMENTAL ANIMAL MODELS for diseases (DISEASE MODELS, ANIMAL) and to clarify the functions of the genes.Hepatocytes: The main structural component of the LIVER. They are specialized EPITHELIAL CELLS that are organized into interconnected plates called lobules.Biotransformation: The chemical alteration of an exogenous substance by or in a biological system. The alteration may inactivate the compound or it may result in the production of an active metabolite of an inactive parent compound. The alterations may be divided into METABOLIC DETOXICATION, PHASE I and METABOLIC DETOXICATION, PHASE II.Structure-Activity Relationship: The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups.Chlorodiphenyl (54% Chlorine)Transcriptional Activation: Processes that stimulate the GENETIC TRANSCRIPTION of a gene or set of genes.Gene Expression: The phenotypic manifestation of a gene or genes by the processes of GENETIC TRANSCRIPTION and GENETIC TRANSLATION.Response Elements: Nucleotide sequences, usually upstream, which are recognized by specific regulatory transcription factors, thereby causing gene response to various regulatory agents. These elements may be found in both promoter and enhancer regions.Hydrocarbons, Alicyclic: Organic compounds composed exclusively of carbon and hydrogen. Three or more carbon atoms are arranged in a cyclic structure and they possess aliphatic properties.Cloning, Molecular: The insertion of recombinant DNA molecules from prokaryotic and/or eukaryotic sources into a replicating vehicle, such as a plasmid or virus vector, and the introduction of the resultant hybrid molecules into recipient cells without altering the viability of those cells.Substrate Specificity: A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts.Alkenes: Unsaturated hydrocarbons of the type Cn-H2n, indicated by the suffix -ene. (Grant & Hackh's Chemical Dictionary, 5th ed, p408)PhenanthrenesHydrocarbons, Acyclic: Organic compounds composed exclusively of carbon and hydrogen where no carbon atoms join to form a ring structure.Hydroxybenzoates: Benzoate derivatives substituted by one or more hydroxy groups in any position on the benzene ring.Promoter Regions, Genetic: DNA sequences which are recognized (directly or indirectly) and bound by a DNA-dependent RNA polymerase during the initiation of transcription. Highly conserved sequences within the promoter include the Pribnow box in bacteria and the TATA BOX in eukaryotes.Genes, Reporter: Genes whose expression is easily detectable and therefore used to study promoter activity at many positions in a target genome. In recombinant DNA technology, these genes may be attached to a promoter region of interest.Beluga Whale: The species Delphinapterus leucas, in the family Monodontidae, found primarily in the Arctic Ocean and adjoining seas. They are small WHALES lacking a dorsal fin.Growth Hormone-Secreting Pituitary Adenoma: A pituitary tumor that secretes GROWTH HORMONE. In humans, excess HUMAN GROWTH HORMONE leads to ACROMEGALY.Biopterin: A natural product that has been considered as a growth factor for some insects.Sequence Homology, Amino Acid: The degree of similarity between sequences of amino acids. This information is useful for the analyzing genetic relatedness of proteins and species.Receptor Cross-Talk: The simultaneous or sequential binding of multiple cell surface receptors to different ligands resulting in coordinated stimulation or suppression of signal transduction.Environmental Monitoring: The monitoring of the level of toxins, chemical pollutants, microbial contaminants, or other harmful substances in the environment (soil, air, and water), workplace, or in the bodies of people and animals present in that environment.Blotting, Western: Identification of proteins or peptides that have been electrophoretically separated by blot transferring from the electrophoresis gel to strips of nitrocellulose paper, followed by labeling with antibody probes.DNA Primers: Short sequences (generally about 10 base pairs) of DNA that are complementary to sequences of messenger RNA and allow reverse transcriptases to start copying the adjacent sequences of mRNA. Primers are used extensively in genetic and molecular biology techniques.Luciferases: Enzymes that oxidize certain LUMINESCENT AGENTS to emit light (PHYSICAL LUMINESCENCE). The luciferases from different organisms have evolved differently so have different structures and substrates.Azo CompoundsLiver Neoplasms, Experimental: Experimentally induced tumors of the LIVER.Smoke25-Hydroxyvitamin D3 1-alpha-Hydroxylase: A mitochondrial cytochrome P450 enzyme that catalyzes the 1-alpha-hydroxylation of 25-hydroxyvitamin D3 (also known as 25-hydroxycholecalciferol) in the presence of molecular oxygen and NADPH-FERRIHEMOPROTEIN REDUCTASE. This enzyme, encoded by CYP27B1 gene, converts 25-hydroxyvitamin D3 to 1-alpha,25-dihydroxyvitamin D3 which is the active form of VITAMIN D in regulating bone growth and calcium metabolism. This enzyme is also active on plant 25-hydroxyvitamin D2 (ergocalciferol).Flavones: A group of 4-keto-FLAVONOIDS.Fuel Oils: Complex petroleum hydrocarbons consisting mainly of residues from crude oil distillation. These liquid products include heating oils, stove oils, and furnace oils and are burned to generate energy.Transfection: The uptake of naked or purified DNA by CELLS, usually meaning the process as it occurs in eukaryotic cells. It is analogous to bacterial transformation (TRANSFORMATION, BACTERIAL) and both are routinely employed in GENE TRANSFER TECHNIQUES.Benzene DerivativesReceptors, Drug: Proteins that bind specific drugs with high affinity and trigger intracellular changes influencing the behavior of cells. Drug receptors are generally thought to be receptors for some endogenous substance not otherwise specified.7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide: 7,8,8a,9a-Tetrahydrobenzo(10,11)chryseno (3,4-b)oxirene-7,8-diol. A benzopyrene derivative with carcinogenic and mutagenic activity.Zebrafish: An exotic species of the family CYPRINIDAE, originally from Asia, that has been introduced in North America. They are used in embryological studies and to study the effects of certain chemicals on development.Steroids, Brominated: Steroids which are substituted with one or more bromine atoms in any position.Hep G2 Cells: A human liver tumor cell line used to study a variety of liver-specific metabolic functions.Pseudomonas putida: A species of gram-negative, aerobic bacteria isolated from soil and water as well as clinical specimens. Occasionally it is an opportunistic pathogen.4-Hydroxybenzoate-3-Monooxygenase: A flavoprotein that catalyzes the synthesis of protocatechuic acid from 4-hydroxybenzoate in the presence of molecular oxygen. EC 1.14.13.2.Protein Structure, Tertiary: The level of protein structure in which combinations of secondary protein structures (alpha helices, beta sheets, loop regions, and motifs) pack together to form folded shapes called domains. Disulfide bridges between cysteines in two different parts of the polypeptide chain along with other interactions between the chains play a role in the formation and stabilization of tertiary structure. Small proteins usually consist of only one domain but larger proteins may contain a number of domains connected by segments of polypeptide chain which lack regular secondary structure.Species Specificity: The restriction of a characteristic behavior, anatomical structure or physical system, such as immune response; metabolic response, or gene or gene variant to the members of one species. It refers to that property which differentiates one species from another but it is also used for phylogenetic levels higher or lower than the species.Gasoline: Volative flammable fuel (liquid hydrocarbons) derived from crude petroleum by processes such as distillation reforming, polymerization, etc.Mutation: Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.Time Factors: Elements of limited time intervals, contributing to particular results or situations.Phenobarbital: A barbituric acid derivative that acts as a nonselective central nervous system depressant. It potentiates GAMMA-AMINOBUTYRIC ACID action on GABA-A RECEPTORS, and modulates chloride currents through receptor channels. It also inhibits glutamate induced depolarizations.Sequence Alignment: The arrangement of two or more amino acid or base sequences from an organism or organisms in such a way as to align areas of the sequences sharing common properties. The degree of relatedness or homology between the sequences is predicted computationally or statistically based on weights assigned to the elements aligned between the sequences. This in turn can serve as a potential indicator of the genetic relatedness between the organisms.Stilbenes: Organic compounds that contain 1,2-diphenylethylene as a functional group.Recombinant Proteins: Proteins prepared by recombinant DNA technology.Cobalt: A trace element that is a component of vitamin B12. It has the atomic symbol Co, atomic number 27, and atomic weight 58.93. It is used in nuclear weapons, alloys, and pigments. Deficiency in animals leads to anemia; its excess in humans can lead to erythrocytosis.Carbazoles: Benzo-indoles similar to CARBOLINES which are pyrido-indoles. In plants, carbazoles are derived from indole and form some of the INDOLE ALKALOIDS.DNA: A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine).Chrysenes: 1,2-Benzphenanthrenes. POLYCYCLIC COMPOUNDS obtained from coal tar.Oxidation-Reduction: A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471).Nuclear Proteins: Proteins found in the nucleus of a cell. Do not confuse with NUCLEOPROTEINS which are proteins conjugated with nucleic acids, that are not necessarily present in the nucleus.Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ASCORBIC ACID can result in impaired hydroxyproline formation.Chromatography, High Pressure Liquid: Liquid chromatographic techniques which feature high inlet pressures, high sensitivity, and high speed.Amino Acids, Aromatic: Amino acids containing an aromatic side chain.Tumor Cells, Cultured: Cells grown in vitro from neoplastic tissue. If they can be established as a TUMOR CELL LINE, they can be propagated in cell culture indefinitely.Isoenzymes: Structurally related forms of an enzyme. Each isoenzyme has the same mechanism and classification, but differs in its chemical, physical, or immunological characteristics.Petroleum Pollution: Release of oil into the environment usually due to human activity.Proline: A non-essential amino acid that is synthesized from GLUTAMIC ACID. It is an essential component of COLLAGEN and is important for proper functioning of joints and tendons.Oxidoreductases: The class of all enzymes catalyzing oxidoreduction reactions. The substrate that is oxidized is regarded as a hydrogen donor. The systematic name is based on donor:acceptor oxidoreductase. The recommended name will be dehydrogenase, wherever this is possible; as an alternative, reductase can be used. Oxidase is only used in cases where O2 is the acceptor. (Enzyme Nomenclature, 1992, p9)Models, Molecular: Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures.Fumarate Hydratase: An enzyme that catalyzes the reversible hydration of fumaric acid to yield L-malic acid. It is one of the citric acid cycle enzymes. EC 4.2.1.2.Indoles: Benzopyrroles with the nitrogen at the number one carbon adjacent to the benzyl portion, in contrast to ISOINDOLES which have the nitrogen away from the six-membered ring.DNA, Complementary: Single-stranded complementary DNA synthesized from an RNA template by the action of RNA-dependent DNA polymerase. cDNA (i.e., complementary DNA, not circular DNA, not C-DNA) is used in a variety of molecular cloning experiments as well as serving as a specific hybridization probe.Models, Biological: Theoretical representations that simulate the behavior or activity of biological processes or diseases. For disease models in living animals, DISEASE MODELS, ANIMAL is available. Biological models include the use of mathematical equations, computers, and other electronic equipment.Cytosol: Intracellular fluid from the cytoplasm after removal of ORGANELLES and other insoluble cytoplasmic components.Glucuronosyltransferase: A family of enzymes accepting a wide range of substrates, including phenols, alcohols, amines, and fatty acids. They function as drug-metabolizing enzymes that catalyze the conjugation of UDPglucuronic acid to a variety of endogenous and exogenous compounds. EC 2.4.1.17.p-Aminoazobenzene: Used in the form of its salts as a dye and as an intermediate in manufacture of Acid Yellow, diazo dyes, and indulines.Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.Ovulation Inhibition: Blocking the process leading to OVULATION. Various factors are known to inhibit ovulation, such as neuroendocrine, psychological, and pharmacological agents.Kaempferols: A group of FLAVONOLS based on kaempferol. They are derived from naringenin and can be hydroxylated to QUERCETIN or reduced to leucopelargonidin.Intracellular Signaling Peptides and Proteins: Proteins and peptides that are involved in SIGNAL TRANSDUCTION within the cell. Included here are peptides and proteins that regulate the activity of TRANSCRIPTION FACTORS and cellular processes in response to signals from CELL SURFACE RECEPTORS. Intracellular signaling peptide and proteins may be part of an enzymatic signaling cascade or act through binding to and modifying the action of other signaling factors.Adipates: Derivatives of adipic acid. Included under this heading are a broad variety of acid forms, salts, esters, and amides that contain a 1,6-carboxy terminated aliphatic structure.Pteridines: Compounds based on pyrazino[2,3-d]pyrimidine which is a pyrimidine fused to a pyrazine, containing four NITROGEN atoms.Cell Nucleus: Within a eukaryotic cell, a membrane-limited body which contains chromosomes and one or more nucleoli (CELL NUCLEOLUS). The nuclear membrane consists of a double unit-type membrane which is perforated by a number of pores; the outermost membrane is continuous with the ENDOPLASMIC RETICULUM. A cell may contain more than one nucleus. (From Singleton & Sainsbury, Dictionary of Microbiology and Molecular Biology, 2d ed)NAD(P)H Dehydrogenase (Quinone): A flavoprotein that reversibly catalyzes the oxidation of NADH or NADPH by various quinones and oxidation-reduction dyes. The enzyme is inhibited by dicoumarol, capsaicin, and caffeine.Coal Tar: A by-product of the destructive distillation of coal used as a topical antieczematic. It is an antipruritic and keratoplastic agent used also in the treatment of psoriasis and other skin conditions. Occupational exposure to soots, tars, and certain mineral oils is known to be carcinogenic according to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985) (Merck Index, 11th ed).Mimosine: 3-Hydroxy-4-oxo-1(4H)-pyridinealanine. An antineoplastic alanine-substituted pyridine derivative isolated from Leucena glauca.Binding, Competitive: The interaction of two or more substrates or ligands with the same binding site. The displacement of one by the other is used in quantitative and selective affinity measurements.COS Cells: CELL LINES derived from the CV-1 cell line by transformation with a replication origin defective mutant of SV40 VIRUS, which codes for wild type large T antigen (ANTIGENS, POLYOMAVIRUS TRANSFORMING). They are used for transfection and cloning. (The CV-1 cell line was derived from the kidney of an adult male African green monkey (CERCOPITHECUS AETHIOPS).)Gas Chromatography-Mass Spectrometry: A microanalytical technique combining mass spectrometry and gas chromatography for the qualitative as well as quantitative determinations of compounds.Glutathione Transferase: A transferase that catalyzes the addition of aliphatic, aromatic, or heterocyclic FREE RADICALS as well as EPOXIDES and arene oxides to GLUTATHIONE. Addition takes place at the SULFUR. It also catalyzes the reduction of polyol nitrate by glutathione to polyol and nitrite.Mice, Inbred DBAChromatin Immunoprecipitation: A technique for identifying specific DNA sequences that are bound, in vivo, to proteins of interest. It involves formaldehyde fixation of CHROMATIN to crosslink the DNA-BINDING PROTEINS to the DNA. After shearing the DNA into small fragments, specific DNA-protein complexes are isolated by immunoprecipitation with protein-specific ANTIBODIES. Then, the DNA isolated from the complex can be identified by PCR amplification and sequencing.Steroid 16-alpha-Hydroxylase: A liver microsomal cytochrome P450 enzyme that catalyzes the 16-alpha-hydroxylation of a broad spectrum of steroids, fatty acids, and xenobiotics in the presence of molecular oxygen and NADPH-FERRIHEMOPROTEIN REDUCTASE. This enzyme is encoded by a number of genes from several CYP2 subfamilies.Phylogeny: The relationships of groups of organisms as reflected by their genetic makeup.Flavin-Adenine Dinucleotide: A condensation product of riboflavin and adenosine diphosphate. The coenzyme of various aerobic dehydrogenases, e.g., D-amino acid oxidase and L-amino acid oxidase. (Lehninger, Principles of Biochemistry, 1982, p972)Lung: Either of the pair of organs occupying the cavity of the thorax that effect the aeration of the blood.Repressor Proteins: Proteins which maintain the transcriptional quiescence of specific GENES or OPERONS. Classical repressor proteins are DNA-binding proteins that are normally bound to the OPERATOR REGION of an operon, or the ENHANCER SEQUENCES of a gene until a signal occurs that causes their release.Coke: A residue of coal, left after dry (destructive) distillation, used as a fuel.Phenol: An antiseptic and disinfectant aromatic alcohol.Flavins: Derivatives of the dimethylisoalloxazine (7,8-dimethylbenzo[g]pteridine-2,4(3H,10H)-dione) skeleton. Flavin derivatives serve an electron transfer function as ENZYME COFACTORS in FLAVOPROTEINS.Dimerization: The process by which two molecules of the same chemical composition form a condensation product or polymer.Pharmacognosy: The science of drugs prepared from natural-sources including preparations from PLANTS, animals, and other organisms as well as MINERALS and other substances included in MATERIA MEDICA. The therapeutic usage of plants is PHYTOTHERAPY.Antrodia: A genus of brown-rot fungi in the family Coriolaceae. The biologically active ingredients of its species have potential pharmaceutical value.CarbanilidesGlutaratesToluene: A widely used industrial solvent.

An investigation into the binding of the carcinogen 15,16-dihydro-11-methylcyclopenta[a]phenanthren-17-one to DNA in vitro. (1/3060)

After metabolic activation the carcinogen 15,16-dihydro-11-[3H]methylcyclopenta[a]phenanthren-17-one binds to DNA in vitro, and this binding is prevented by 7,8-benzoflavone. Radioactivity cannot be removed from the DNA with organic solvents or by chromatography on Sephadex G-50, even after heat denaturation of the DNA. Enzymatic hydrolysis yields radioactive fractions, which elute from a column of Sephadex LH-20 immediately after the natural nucleosides. At least two species of reactive metabolites are involved in this bending, those with a half-life of a few hr and others with greater stability. After extraction from the aqueous incubation mixture, they could be detected in discrete polar fractions from separations of the complex metabolite mixture by high-pressure liquid chromatography. Their ability to bind to DNA decreased with time at ambient temperature, and they were rapidly deactivated by acid. 7,8-Benzolflavone acted by suppressing the formation of polar metabolites derived from enzymatic oxidation of the aromatic double bonds. The inhibitor had no effect on the enzymes hydroxylating saturated carbon; hence it is unlikely that metabolism of the methyl group is important in conversion of this carcinogen to its proximate form, although the presence of the 11-methyl group is essential for carcinogenic activity in this series.  (+info)

The repressed nuclear receptor CAR responds to phenobarbital in activating the human CYP2B6 gene. (2/3060)

The endogenous CYP2B6 gene becomes phenobarbital (PB) inducible in androstenol-treated HepG2 cells either transiently or stably transfected with a nuclear receptor CAR expression vector. The PB induction mediated by CAR is regulated by a conserved 51-base pair element called PB-responsive enhancer module (PBREM) that has now been located between -1733 and -1683 bp in the gene's 5'-flanking region. An in vitro translated CAR acting as a retinoid X receptor alpha heterodimer binds directly to the two nuclear receptor sites NR1 and NR2 within PBREM. In a stably transfected HepG2 cell line, both PBREM and NR1 are activated by PB and PB-type compounds such as chlorinated pesticides, polychlorinated biphenyls and chlorpromazine. In addition to PBREM, CAR also transactivates the steroid/rifampicin-response element of the human CYP3A4 gene in HepG2 cells. Thus, activation of the repressed nuclear receptor CAR appears to be a versatile mediator that regulates PB induction of the CYP2B and other genes.  (+info)

Induction of hepatic cytochromes P450 in dogs exposed to a chronic low dose of polychlorinated biphenyls. (3/3060)

Induction of cytochrome P450 isoforms, specifically CYP1A1, and their catalytic activities are potential biomarkers of environmental contamination by polychlorinated biphenyls (PCBs). In this study, dogs were exposed to 25 ppm or 5 ppm Aroclor 1248 (PCB mixture) daily in their diet for 10 or 20 weeks, respectively. Relative to controls, hepatic microsomes from dogs dosed with PCBs had higher levels of CYP1A1 detected in immunoblots and higher levels of EROD activity, but low levels of induction for CYP2B and PROD activity. Concentrations of 96 PCB congeners in serum and liver were evaluated using capillary chromatography. Results showed that all dogs exposed to PCB mixtures had higher levels of PCB in serum and liver. Dogs preferentially sequestered highly chlorinated PCB congeners in liver relative to serum. With these experiments, we demonstrated that EROD activity was a potentially sensitive marker of PCB exposure at 5 and 25 ppm. Furthermore, CYP1A1 and EROD activity were maximally induced in dogs consuming dietary concentrations only 2.5 times the maximal permissible level for human food (FDA). The value of CYP1A1 induction as a biomarker of PCB exposure was tenuous because neither CYP1A1 levels nor EROD activity correlated with total PCB body burden. However, a small subset of congeners were identified in liver that may strongly influence EROD and PROD induction. Finally, two dogs in the 25 ppm dose group were fasted for 48 h. After 24 h of fasting, several new congeners appeared in the serum and remained in the serum for the remainder of the fast. The fast caused a 293% increase in PCB concentration in serum. This increase has strong implications regarding mobilization of toxic PCBs in wildlife during fasting (e.g., migration, hibernation).  (+info)

Regulation of cytochrome P-450 (CYP) 1B1 in mouse Hepa-1 variant cell lines: A possible role for aryl hydrocarbon receptor nuclear translocator (ARNT) as a suppressor of CYP1B1 gene expression. (4/3060)

Cytochrome P-450 (CYP) 1B1 expression in mouse hepatoma (Hepa-1) wild-type (WT) cells was compared with responses in Hepa-1 variants LA1 and LA2, which, respectively, exhibit low aryl hydrocarbon receptor (AhR) level and defective AhR nuclear translocator (ARNT) protein. 10T1/2 mouse embryo fibroblasts express predominantly CYP1B1 and at a 100 times higher level than in Hepa-1 cells, whereas they express about 300-fold lower CYP1A1 than Hepa-1 cells. The expression of CYP1B1 in WT and LA1 variant, although at a much lower level, follows that of CYP1A1, reflecting their common regulation through the AhR. The LA2 (ARNT-defective) cells showed a major difference between CYP1B1 and CYP1A1 expression. Although CYP1A1 mRNA levels in LA2 were extremely low and unresponsive to 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD), basal CYP1B1 mRNA and protein were expressed at levels similar to those seen in TCDD-induced WT. The elevated basal CYP1B1 mRNA in LA2 cells decreased by 50% after transient transfection of ARNT cDNA, in parallel with substantial restoration of CYP1A1 induction. This implicates ARNT as a suppressor of CYP1B1 basal expression in Hepa cells. In transient CYP1B1-luciferase constructs in LA2 cells, ARNT shows stimulatory effects in the enhancer region but an inhibitory effect on the proximal promoter. Two CYP1B1 enhancer elements [xenobiotic-responsive element (XRE) 1/2 and XRE4] formed TCDD-unresponsive complexes of similar mobility to TCDD-stimulated AhR-ARNT complex with XRE5. However, because these two complexes were formed to the same extent in LA2 as in WT cells, they cannot be due to ARNT or contribute to ARNT-regulated suppression.  (+info)

Cytochrome P450 CYP1B1 determines susceptibility to 7, 12-dimethylbenz[a]anthracene-induced lymphomas. (5/3060)

CYP1B1-null mice, created by targeted gene disruption in embryonic stem cells, were born at the expected frequency from heterozygous matings with no observable phenotype, thus establishing that CYP1B1 is not required for mouse development. CYP1B1 was not detectable in cultured embryonic fibroblast (EF) or in different tissues, such as lung, of the CYP1B1-null mouse treated with the aryl hydrocarbon receptor agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin whereas the equivalent wild-type EF cells express basal and substantial inducible CYP1B1 and lung expresses inducible CYP1B1. CYP1A1 is induced to far higher levels than CYP1B1 in liver, kidney, and lung in wild-type mice and is induced to a similar extent in CYP1B1-null mice. 7,12-dimethylbenz[a]anthracene (DMBA) was toxic in wild-type EFs that express CYP1B1 but not CYP1A1. These cells effectively metabolized DMBA, consistent with CYP1B1 involvement in producing the procarcinogenic 3,4-dihydrodiol as a major metabolite, whereas CYP1B1-null EF showed no significant metabolism and were resistant to DMBA-mediated toxicity. When wild-type mice were administered high levels of DMBA intragastrically, 70% developed highly malignant lymphomas whereas only 7.5% of CYP1B1-null mice had lymphomas. Skin hyperplasia and tumors were also more frequent in wild-type mice. These results establish that CYP1B1, located exclusively at extrahepatic sites, mediates the carcinogenicity of DMBA. Surprisingly, CYP1A1, which has a high rate of DMBA metabolism in vitro, is not sufficient for this carcinogenesis, which demonstrates the importance of extrahepatic P450s in determining susceptibility to chemical carcinogens and validates the search for associations between P450 expression and cancer risk in humans.  (+info)

Effect of cryopreservation on cytochrome P-450 enzyme induction in cultured rat hepatocytes. (6/3060)

In the present study, we evaluated the inducibility of cytochrome P-450 (CYP) CYP1A, CYP2B, CYP3A, and CYP4A by beta-naphthoflavone, phenobarbital, dexamethasone, and clofibric acid, respectively, in primary hepatocyte cultures prepared from both fresh and cryopreserved rat hepatocytes. Rat hepatocytes were successfully thawed and cultured after cryopreservation in liquid nitrogen for up to 1 month. Percentage of total recovery, viable cell recovery, and final viability of the cells were 68%, 72%, and 85%, respectively. Regardless of whether they were cryopreserved or not, cultured hepatocytes exhibited near-normal morphology. Treatment of cryopreserved hepatocytes with beta-naphthoflavone caused an 8-fold increase in 7-ethoxyresorufin O-dealkylase (CYP1A1/2) activity, with an EC50 of 1.5 microM; treatment with phenobarbital caused a 26-fold increase in 7-pentoxyresorufin O-dealkylase (CYP2B1/2) activity, with an EC50 of 10 microM; treatment with dexamethasone caused a 10-fold increase in testosterone 6beta-hydroxylase (CYP3A1/2) activity, with an EC50 of 1.3 microM, whereas treatment with clofibric acid caused a 3-fold increase in lauric acid 12-hydroxylase (CYP4A1-3) activity, with an EC50 of 170 microM. The induction of CYP1A, CYP2B, CYP3A, and CYP4A enzymes by these inducers was confirmed by Western immunoblotting. The patterns of P-450 induction in cryopreserved rat hepatocytes, in terms of concentration response, reproducibility, magnitude, and specificity of response, were similar to those observed in freshly isolated hepatocytes. Additionally, the magnitude and specificity of induction was similar to that observed in vivo in rats. In conclusion, under the conditions examined, cryopreserved rat hepatocytes appear to be a suitable in vitro system for evaluating xenobiotics as inducers of P-450 enzymes.  (+info)

The aromatase inactivator 4-hydroxyandrostenedione (4-OH-A) inhibits tamoxifen metabolism by rat hepatic cytochrome P-450 3A: potential for drug-drug interaction of tamoxifen and 4-OH-A in combined anti-breast cancer therapy. (7/3060)

Tamoxifen (tam), an anti-breast cancer agent, is metabolized into tam-N-oxide by the hepatic flavin-containing monooxygenase and into N-desmethyl- and 4-hydroxy-tam by cytochrome P-450s (CYPs). Additionally, tam is metabolically activated by hepatic CYP3A, forming a reactive intermediate that binds covalently to proteins. Tam and 4-hydroxyandrostenedione (4-OH-A) are currently used to treat breast cancer, and it has been contemplated that 4-OH-A be given concurrently with tam to contravene potential tumor resistance to tam. Because alterations in tam metabolism may influence its therapeutic efficacy, the effect of 4-OH-A on tam metabolism was examined. Incubation of tam with liver microsomes from phenobarbital-treated rats, in the presence of 4-OH-A (10-100 microM), resulted in marked inhibition of tam-N-demethylation and tam covalent binding and in decreased tam-N-oxide accumulation; however, there was no inhibition of the formation of 4-hydroxy-tam and of 3,4-dihydroxytamoxifen. These findings indicate that 4-OH-A inhibits CYP3A, but not P-450(s) that catalyze tam 4-hydroxylation. The diminished tam-N-oxide accumulation could be due to decreased N-oxide formation and/or due to increased N-oxide reduction. Incubation of tam-N-oxide with liver microsomes containing heat-inactivated flavin-containing monooxygenase demonstrated that 4-OH-A increases the accumulation of tam, possibly by diminishing its P-450-mediated metabolism. Kinetic studies indicate that 4-OH-A is a competitive inhibitor of CYP3A, but not a time-dependent inactivator. Consequently, the concurrent treatment of tam and 4-OH-A may result in increased tam half-life and thus could potentiate the therapeutic efficacy of tam and diminish the potential side effects of tam by inhibiting its covalent binding to proteins and possibly to DNA.  (+info)

Quantitative analysis of constitutive and 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced cytochrome P450 1B1 expression in human lymphocytes. (8/3060)

Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin) results in a broad spectrum of biological responses, including altered metabolism, disruption of normal hormone signaling pathways, reproductive and developmental effects, and cancer. Cytochrome P450 1B1 (CYP1B1) is a dioxin-inducible gene that is active in the formation of 4-hydroxyestradiol, a potentially genotoxic catechol estrogen. Therefore, the analysis of CYP1B1 in humans may be useful in establishing relationships between dioxin exposure and adverse health effects. In this study, we examined the expression of CYP1B1 in human peripheral blood lymphocytes of unexposed individuals using a quantitative reverse transcription-PCR method. Absolute CYP1B1 RNA levels varied more than 30-fold in uncultured mononuclear cells obtained from 10 individuals. In vitro treatment of mitogen-stimulated lymphocytes with TCDD for 1-5 days of culture resulted in a peak induction of CYP1B1 after 3 days. The induction of CYP1B1 RNA levels after 3 days of culture was dose-dependent, exhibited a maximum response above 10 nM TCDD, and varied greatly among different individuals. However, the half maximal dose required for this induction was similar between individuals and comparable to that observed in the MCF-7 and HepG2 human cell lines. These observations indicate that CYP1B1 exhibits variable constitutive expression and is inducible in vitro by TCDD in human lymphocytes and that the magnitude of induction varies within the population. These data define the suitability of CYP1B1 for use as a mechanistically based biomarker in ongoing molecular epidemiological studies of human populations exposed to dioxins and related chemicals that bind the aromatic hydrocarbon receptor.  (+info)

We measured aryl hydrocarbon hydroxylase (AHH) in cultured human lymphocytes. A striking seasonal variation in AHH activity was observed with induced AHH activity levels from January through May measuring approximately 20% of the values during the remainder of the year. AHH inducibility was determined by comparing lymphocytes from the same person cultured with and without the inducer 3-methylcholanthrene. If measurements are limited to the summer and fall seasons when AHH activity is high, AHH inducibility is reproducible for most persons with repeat determinations on the same person averaging 11% from the mean. The values of AHH inducibility in 53 persons ranged from 0.9 to 5.0, but the distribution of values did not fall into three distinct, nonoverlapping classes as reported by others. We were not able to determine the distribution of AHH inducibility in lung cancer patients since lymphocytes from less than half of the patients tested could be successfully cultured.
Environmental exposure to carcinogens may contribute to increasing breast cancer rates and geographic variation in breast cancer incidence in the United States. One class of chemicals that has received much attention are the polyaromatic hydrocarbons that are ubiquitous in the environment and occur in cigarette smoke. The cytochrome P450 1A1 (CYP1A1) gene codes for an enzyme that contributes to aryl hydrocarbon hydroxylase activity, which is involved in the metabolism of polyaromatic hydrocarbons. Genotypic variants of CYP1A1 have been associated with increased aryl hydrocarbon hydroxylase activity, and some epidemiological studies suggest that women with the variant genotype(s) are at increased risk for breast cancer.. We prospectively evaluated the associations between the CYP1A1 polymorphisms and breast cancer risk, as well as the potential modification of these associations by cigarette smoking, in a case-control study nested within the Nurses Health Study. We analyzed the T→C transition ...
Closer evaluation of the superimposed SIRT2 structures revealed that the amide group of 6 might occupy the same space as the methyl group of the Nε-acetyl-lysine substrate (Fig. 3). This result prompted us to take a new perspective toward targeting the substrate-binding site through the functionalization of the benzamide moiety in 6 to mimic the acetyl-lysine interactions, which afforded compounds 17-19, 26-28, 36, 41 and 42 (Fig. 4). All compounds prepared in this study (Schemes S1-4†) were screened in vitro against SIRT1-3 and SIRT5 (concentration: 10 μM; Table 1), while 6, UKU10363 (Fig. 4) and 5 were used as reference compounds. In a first attempt to mimic the lysine acetyl amide, we explored small fragments using a glycinamide linker (17-19). The screening of SIRT1-3 and 5 (Table 1) revealed that both isotype selectivity and good SIRT2 inhibitory activity were retained upon amide functionalization of 6, although the inhibitory potency was not improved. In order to rationalize the ...
Some, but by no means most, of the individual variability in the rate at which nicotine is metabolized can be explained by CYP2A6 SNPs. Generally, smokers whose bodies rapidly metabolize nicotine will smoke more cigarettes, take in more cigarette smoke, and be more resistant to kicking the habit than slower metabolizers. The most common CYP2A6 allele, CYP2A6*1, is considered to give rise to a fast metabolizing phenotype. Four relatively common CYP2A6 alleles are associated with slower metabolizers; they are CYP2A6*2, CYP2A6*4, CYP2A6*9, and CYP2A6*12. [PMID 17112802] CYP2A6*5 is a rare non-functioning variant. [PMID 15993850] The CYP2A6*20 variant results in a truncated protein and no enzyme activity. To be more precise, the estimated percentage of CYP2A6 activity by genotype is as follows: ...
To test whether the distribution of AHH inducibility is shifted toward the high end of the range in patients who had lung and laryngeal cancer, we measured this trait in 59 patients (32 lung and 27 laryngeal) who had resectable tumors and had been disease-free for a period of time. The advantage of selecting patients who were free of clinical disease was that measurement of their AHH inducibility should not have been affected by the disease state. Patient and control populations showed no difference in basal and induced AHH activity of AHH inducibility. The mean AHH inducibility in patients who had lung cancer was 3.20 +/- 0.20; in patients who had laryngeal cancer 2.96 +/- 0.18, and for all controls 3.29 +/- 0.04 (no significant difference at p = 0 05). Further analysis of the distribution of AHH inducibility in the patient group compared to controls showed no suggestion of a shift toward the higher end of the range in patients who had lung and laryngeal cancer.
TY - JOUR. T1 - Metabolic activation of aromatic hydrocarbons in purified rat liver nuclei. T2 - induction of enzyme activities and binding to DNA with and without monooxygenase catalyzed formation of active oxygen. AU - Rogan, Eleanor G. AU - Mailander, P.. AU - Cavalieri, Ercole. PY - 1976/1/1. Y1 - 1976/1/1. N2 - Purified rat liver nuclei covalently bound low levels of seven aromatic [14C]hydrocarbons to nuclear DNA. Iduction with 3 methylcholanthrene increased the binding of six carcinogenic hydrocarbons, but did not raise the level of binding of noncarcinogenic anthracene. Removal of the nuclear envelope by Triton N 101 eliminated binding and aryl hydrocarbon hydroxylase activities and cytochrome P 450 from the nuclei. Binding of two strong carcinogens, benzo[α]pyrene and 7,12 dimethylbenz[α]anthracene, to nuclear DNA was compared to the levels of aryl hydrocarbon hydroxylase and cytochrome P 450 in nuclei from uninduced and benz[α]anthracene, 3 methylcholanthrene, and phenobarbital ...
MalaCards based summary : Cyp1b1-Related Primary Congenital Glaucoma is related to primary congenital glaucoma. An important gene associated with Cyp1b1-Related Primary Congenital Glaucoma is CYP1B1 (Cytochrome P450 Family 1 Subfamily B Member 1 ...
The response of intestinal monooxygenases to dietary polycyclic aromatic hydrocarbon (PAH) exposure was evaluated in spot (Leiostomus xanthurus), a marine teleost fish. Ethoxyresorufin O-deethylase (EROD) and aryl hydrocarbon hydroxylase (AHH) activities were highest in the pyloric caeca and in the proximal half of the intestine. Intestinal microsomes from fish given control diets had very low levels of EROD and AHH activities relative to those in liver. After exposure to a diet containing 10 mg of 3-methylcholanthrene/kg of food, the levels of intestinal EROD and AHH activities increased 36-fold and 17-fold, respectively, such that intestinal monooxygenase activity exceeded that of the liver, which was not induced by this treatment. A significant increase in intestinal monooxygenase activity occurred in fish receiving dietary benzo[a]pyrene (BP) at concentrations as low as 10 micrograms of BP/kg food. A 5-fold increase in intestinal AHH and EROD activities was observed within 3 hr after ...
The c1 (B6NLxv1c2) line was derived from Hepa-1c1c7 (ATCC CRL-2026). Hepa-1c1c7 has high CYP1A1-dependent aryl hydrocarbon hydroxylase (AHH) activity. N-methyl-N-nitro-N-nitrosoguanidine (MNNS) mutated colonies were selected for benzo[a]pyrene resistance. The c1 (B6NLxv1c2) cell line lacks cytochrome P4501A1 dependent aryl hydrocarbon hydroylase (AHH) activity due to a single point mutation in CYP1A1 leading to premature termination of the translated protein (Asn-414; 56 kDa to 45 kDa). The line may be used to study xenobiotic (and carcinogenic) metabolism in the absence of cytochrome P4501A1 activity, which is known to metabolize cytotoxic and carcinogenic intermediates. It is also a tool to study the putative natural ligand for the induction of this enzyme.
Experimental results, as well as theoretical approaches, indicate one route for substrate access, pw2a, that is common to P450s. Pw2a may also serve as a product egress route in some P450s (Gerber, 1994; Lüdemann et al, 2000a, 2000b; Prasad et al, 2000; Mueller et al, 2003), such as soluble bacterial proteins. However, for membrane‐bound P450s, the pws for product egress and substrate access are likely to differ. A hydrophobic substrate is likely to enter the active site of the enzyme from the membrane, along pw2a; a hydroxylated water‐soluble product is likely to be released into the cytoplasm and requires a different pathway (Fig 2).. The number of crystal structures of mammalian P450s available is limited and the enzymatic mechanism of membrane‐bound P450s is poorly understood. Recently, the first crystal structure of a mammalian membrane‐associated P450 (CYP2C5) in complex with a substrate, 4‐methyl‐N‐methyl‐N‐(2‐phenyl‐2H‐pyrazol‐3‐yl) benzenesulphonamide (DMZ), ...
Increasing use of zebrafish in drug discovery and mechanistic toxicology demands knowledge of cytochrome P450 (CYP) gene regulation and function. CYP enzymes catalyze oxidative transformation leading to activation or inactivation of many endogenous and exogenous chemicals, with consequences for normal physiology and disease processes. Many CYPs potentially have roles in developmental specification, and many chemicals that cause developmental abnormalities are substrates for CYPs. Here we identify and annotate the full suite of CYP genes in zebrafish, compare these to the human CYP gene complement, and determine the expression of CYP genes during normal development. Zebrafish have a total of 94 CYP genes, distributed among 18 gene families found also in mammals. There are 32 genes in CYP families 5 to 51, most of which are direct orthologs of human CYPs that are involved in endogenous functions including synthesis or inactivation of regulatory molecules. The high degree of sequence similarity ...
Trichloroepoxypropane: A potent epoxide hydrase and aryl hydrocarbon hydroxylase inhibitor. It enhances the tumor-initiating ability of certain carcinogens.
Authors: Goldstone, J.V., A.G. McArthur, A. Kubota, J. Zanette, T. Parente, M. Jönsson, D.R. Nelson, & J.J. Stegeman. BMC Genomics 2010, 11: 643.. Increasing use of zebrafish in drug discovery and mechanistic toxicology demands knowledge of cytochrome P450 (CYP) gene regulation and function. CYP enzymes catalyze oxidative transformation leading to activation or inactivation of many endogenous and exogenous chemicals, with consequences for normal physiology and disease processes. Many CYPs potentially have roles in developmental specification, and many chemicals that cause developmental abnormalities are substrates for CYPs. Here we identify and annotate the full suite of CYP genes in zebrafish, compare these to the human CYP gene complement, and determine the expression of CYP genes during normal development. Zebrafish have a total of 94 CYP genes, distributed among 18 gene families found also in mammals. There are 32 genes in CYP families 5 to 51, most of which are direct orthologs of human ...
CYP46A1 antibody [N1C2] (cytochrome P450, family 46, subfamily A, polypeptide 1) for WB. Anti-CYP46A1 pAb (GTX105183) is tested in Mouse samples. 100% Ab-Assurance.
CYP2E1 antibody [9E6] (cytochrome P450, family 2, subfamily E, polypeptide 1) for ICC/IF, IHC-P, WB. Anti-CYP2E1 mAb (GTX84635) is tested in Human samples. 100% Ab-Assurance.
This thing that the doc said hed done thousands of times before and would only take a minute was an ordeal. Apparently I am a "fast metabolizer" of anesthetics. This means that it takes more than the usual patient to where I cant feel anything. Of course this also means more shots! Whats the way to determine that one is a fast metabolizer? Have someone start cutting something off your head so that you can say, "OW!!" I am not exaggerating...FOUR shots later, I finally dont feel anything and he was able to run me over the deli slicer. Ok, so he didnt do that, but it was pretty bad! When I was able to sit up, I turned a little pale and they wouldnt let me up right away, Sylvia looked at the spot on my head and grimaced. She tried to hide it but I could tell. She was a little horrified. I finally got out of her that there was a good sized lump on my head where he took it off. I said, "Of course theres a lump! Thats what happens when you pump a quart and a half of Novocaine into someones ...
ウサギ・ポリクローナル抗体 ab95047 交差種: Ms,Hu 適用: WB,IHC-P,Flow Cyt…CYP27B1抗体一覧…画像、プロトコール、文献などWeb上の情報が満載のアブカムの Antibody 製品。国内在庫と品質保証制度も充実。
The research and development of new drugs is a complex time-and cost-consuming process. Today the mechanism-based approach dominates.
Rabbit anti-human cytochrome P450 enzyme CYP3A4 (polyclonal antibody). Heme-thiolate monooxygenase, involved in metabolism of several steroids, fatty acids, and xenobiotics. CYP3A4 & 5 are the two most predominant proteins within the CYP3A subfamily in human adults, which are collectively involved with the biotransformation of 50% of oxidatively metabolised drugs1. CODE NUMBER: R2X.. QUANTITY: 0.1 mL.. SPECIFICITY: Reacts with human cytochrome P450 enzyme CYP3A4 in hepatic microsomal. fraction from adult donors. Also binds to the fetal form: CYP3A7. No cross-reactivity with CYP3A5.. IMMUNOGEN: Synthetic peptide.. SUGGESTED APPLICATIONS: Western blot, immunohistochemistry on frozen and formaldehyde treated sections. Optimal working dilutions must be determined by end user.. SPECIES REACTIVITY: Human.. FORMAT: Rabbit antiserum.. PRESENTATION: Liquid. No preservatives.. STORAGE/HANDLING: Maintain at -20°C in undiluted aliquots for up to 12 months. Avoid repeated freeze/thaw cycles.. For research ...
Using AGM as a model, we found that long-term, in vivo nicotine treatment significantly decreases in vitro nicotine metabolism by approximately 40% and the expression of a CYP2A6-like protein in AGM liver by approximately 60%. Because nicotine metabolism is dose-independent at the levels of nicotine self-administered by smokers (Benowitz and Jacob, 1993), changes in CYP2A6 protein would be expected to alter nicotine metabolism. Experiments using anti-CYP2A6 inhibitory antibodies strongly suggest that the decrease in nicotine metabolism after long-term nicotine administration is mediated by the decrease observed in the CYP2A6agm-mediated portion of the total NCO (40%), similar to the reduction observed in CYP2A6agm protein (60%). This is quantitatively similar to the decreases in nicotine clearance observed during smoking compared with nonsmoking (27-34%; Lee et al., 1987;Benowitz and Jacob, 1993). Our observation that CYP2A6agm protein and nicotine metabolism is reduced in AGM that underwent ...
Graham, Kirsty, Sparagano, Olivier, Pérez de Léon, Adalberto, Bell-Sakyi, Lesley, Guerrero, F. and Finn, Robert (2012) Identification of Novel Cytochrome P450s in the Acari. In: 19th International Symposium on Microsomes and Drug Oxidations and 12th European ISSX Meeting, 17-21 June, 2012, Noordwijk aan Zee, the Netherlands. Full text not available from this repository. (Request a copy ...
Recombinant Cytochrome P450, Family 1, Subfamily A, Polypeptide 2 (CYP1A2) Protein. Species: Human. Source: Escherichia coli (E. coli). Order product ABIN6303723.
Clopidogrel has anti-platelet activity by irreversible inhibition of the P2Y12 platelet receptor. Clopidogrel must be converted into an active metabolite in order to show anti-platelet activity. Hepatic CYP2C19 enzyme is one of the key hepatic enzymes which convert clopidogrel into active metabolite and its genetic polymorphism is related to clopidogrel resistance. CYP2C19 poor or intermediate metabolizer groups show reduced anti-platelet activity of clopidogrel compared to extensive metabolizer group ...
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Each CypExpress product is comprised of a specific, unmodified recombinant human CYP, P450 oxidoreductase cofactors, and antioxidants encapsulated in a semipermeable shell - allowing rapid diffusion of substrates and products.
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The anticoagulant drug warfarin occurs as a pair of enantiomers that are differentially metabolized by human cytochromes P450 (CYP). R-warfarin is
Recombinant protein of human cytochrome P450, family 51, subfamily A, polypeptide 1 (CYP51A1), 20 ug available for purchase from OriGene - Your Gene Company.
Melet, A., Marques-Soares, C., Schoch, G. A., Macherey, A. C., Jaouen, M., Dansette, P. M., Sari, M. A., Johnson, E. F., Mansuy, D. Analysis of human cytochrome P4502C8 substrate specificity using a substrate pharmacophore and site-directed mutants Biochemistry 2004 43:15379-15392 DOI:10.1021/bi0489309 PMID:15581350 ...
The aim of this study was to investigate the possible effects of EPHX1 and VKORC1L1 polymorphisms on variability of responses to warfarin. Sixteen single nucleotide polymorphisms (SNPs) in 201 patients with stable warfarin doses were analyzed including genes of VKORC1, CYP2C9, CYP4F2, GGCX, EPHX1 and VKORC1L1. Univariate analysis was conducted for the association of genotypes with stable warfarin doses. Multiple linear regression analysis was used to investigate factors that independently affected the inter-individual variability of warfarin dose requirements. The rs4072879 of VKORC1L1 (A , G) was significantly associated with stable warfarin doses; wild homozygote carriers (AA) required significantly lower stable warfarin doses than those with the variant G allele (5.02 ± 1.56 vs. 5.96 ± 2.01 mg; p = 0.001). Multivariate analysis showed that EPHX1 rs1877724 and VKORC1L1 rs4072879 accounted for 1.5% and 1.3% of the warfarin dose variability. Adding EPHX1 and VKORC1L1 SNPs to the base model ...
TY - JOUR. T1 - Selective deficiency of debrisoquine 4-hydroxylase activity in mouse liver microsomes. AU - Masubuchi, Yasuhiro. AU - Iwasa, Takashi. AU - Hosokawa, Shin. AU - Suzuki, Tokuji. AU - Horie, Toshiharu. AU - Imaoka, Susumu. AU - Funae, Yoshihiko. AU - Narimatsu, Shizuo. PY - 1997/9. Y1 - 1997/9. N2 - Cytochrome P450 enzymes belonging to the CYP2D subfamily have been shown to be one of determinants of the polymorphic drug oxidations in the human and the rat. Debrisoquine 4-hydroxylation is a typical reaction catalyzed by these enzymes. However, various strains of mice were observed to have much lower debrisoquine 4-hydroxylase activity than Wistar rats, whereas other monooxygenase activities in mice toward bunitrolol, propranolol, imipramine and amitriptyline, which are mediated by the CYP2D enzymes in the rat, were comparable to those of the rats. Immunoblot analysis of mouse liver microsomes with an antibody raised against a rat CYP2D enzyme indicated that the mouse liver contained ...
Rabbit anti-human cytochrome P450 enzyme CYP2D6 (polyclonal antibody). O-demethylation of xenobiotics, CYP2D6 is involved in the metabolism and elimination of approximately 25% of clinically used drugs in humans1. Primarily expressed in the liver and areas of the CNS. CYP2D1 and CYP2D4 have a similar function in rats2.. CODE NUMBER: RT01.. QUANTITY: 0.1 mL.. SPECIFICITY: Reacts with human cytochrome P450 enzyme CYP2D6 in hepatic microsomal fraction. No cross-reactivity with other cytochrome P450 enzymes.. IMMUNOGEN: Synthetic peptide.. SUGGESTED APPLICATIONS: Western blot, immunohistochemistry on frozen and formaldehyde treated sections. Optimal working dilutions must be determined by end user.. SPECIES REACTIVITY: Human.. FORMAT: Rabbit antiserum.. PRESENTATION: Liquid. No preservatives.. STORAGE/HANDLING: Maintain at -20°C in undiluted aliquots for up to 12 months. Avoid repeated freeze/thaw cycles.. For research use only; not for use in diagnostic procedures. Not for human or animal ...
The anticoagulant effect of warfarin varies greatly among individuals. Some of this variability is attributed to differences in the activity of CYP2C9, the predominant enzyme involved in the metabolism of S-warfarin.. The present study is designed to define the differences in warfarin metabolism among healthy individuals carrying different CYP2C9 genotypes. In addition, the study will define the correlation between the phenytoin metabolic ratio, a marker of CYP2C9 activity in vivo, and warfarin metabolism. ...
There are no specific protocols for Recombinant Human Constitutive androstane receptor protein (ab81846). Please download our general protocols booklet
In this article, we describe the generation and characterization of a novel CYP3A4 humanized mouse line that carries a replacement of the seven chromosomally closely linked murine Cyp3a genes with a large human genomic region carrying CYP3A4 and CYP3A7. A similar approach to replace large sequences of mouse genomic DNA with a syntenic region of human DNA was recently described for the α globin regulatory domain (Wallace et al., 2007). The use of a modified strategy allowed us to generate knockout control mice, Cyp3a(−/−)/3a13(+/+), carrying a deletion of the major part of the mouse Cyp3a cluster. Furthermore, because we used a different selection marker, our approach can be applied to any eukaryotic cell type and can therefore be used widely for the exchange of genomic regions between species.. The targeted insertion strategy applied in the present work distinguishes our huCYP3A4/3A7 model from other existing CYP3A4 humanized mouse lines. Compared with the random transgenic mouse line ...
This study is the first report in which P450s involved in the two oxidative steps required for the metabolism of clopidogrel to its active metabolite are identified and their contributions determined. CYP1A2, CYP2B6, and CYP2C19 are capable of producing 2-oxo-clopidogrel, whereas the remaining isoforms examined were practically inactive in this first oxidative step of clopidogrel. Savi et al. (1994) suggested that rat CYP1A was involved in the active metabolite formation from clopidogrel. The present study confirmed that CYP1A2 does indeed contribute to the first oxidative step of this metabolic process. Regarding the second metabolic step, formation of clopidogrel active metabolite was catalyzed by CYP2B6, CYP2C9, CYP2C19, and CYP3A4. The reaction mixture for the active metabolite formation contained glutathione, because it was previously shown that formation of a thienopyridines active metabolite required the presence of both P450s and a reducing agent such as glutathione in the incubation ...
BioAssay record AID 769674 submitted by ChEMBL: Drug metabolism in human liver microsomes assessed as CYP3A4-mediated metabolite formation in presence of ketaconozole.
BioAssay record AID 510137 submitted by ChEMBL: Ratio of IC50 for CYP3A4 in human liver microsomes measured immediately to IC50 for CYP3A4 in human liver microsomes measured after incubation.
Sigma-Aldrich offers abstracts and full-text articles by [Ramakrishna Nirogi, Raghava Choudary Palacharla, Abdul Rasheed Mohammed, Arunkumar Manoharan, Ranjith Kumar Ponnamaneni, Gopinadh Bhyrapuneni].
Phenytoin (PHT) oxidative route leads to its main metabolite p-hydroxyphenytoin (p-HPPH), by means of CYP2C9 and CYP2C19. Formation of p-HPPH proceeds via a reactive arene-oxide intermediate. This intermediate can also be converted into PHT dihydrodiol by microsomal epoxide hydrolase (EPHX). The three enzymes are polymorphically expressed and the genetic variants are responsible for changes in the enzyme activity. In order to evaluate the effect that these polymorphisms have on PHT metabolism, PHT and p-HPPH plasma concentrations were measured and the genotype for the three enzymes was assessed in 50 Uruguayan epileptic patients. 30% of the patients were intermediate and 2% were poor metabolizers for CYP2C9, while 20% were intermediate metabolizers for CYP2C19. 44%, 10%, and 46% of subjects had intermediate, increased and decreased activities of EPHX respectively. CYP2C9 was confirmed to be the main responsible enzyme for PHT biotransformation. CYP2C19 seemed to be preponderant in p-HPPH oxidative
UMDNJ-Robert Wood Johnson Medical School researchers have found that carbamazepine and oxycarbamazepine increase nicotine metabolism in smokers.
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Large interindividual differences were found in the level of expressed NTCP mRNA obtained from livers of disease-free donors; the difference in expressed mRNA level between the sample exhibiting the lowest level (HL123, Fig. 1) and the highest (HL104, Fig. 1) was 40-fold. In studies of rats, a 10-fold increase in Ntcp mRNA level after prolactin treatment was associated with a 2-fold increase in theVmax value for taurocholate uptake (Liu et al., 1994). Clearly, the measurement of NTCP protein will be an important next step in delineating whether this large variability in NTCP mRNA levels is similarly reflected at the protein level. However, this is currently difficult to determine because a high-affinity antibody against NTCP is not available.. Recombinant vaccinia-mediated expression of NTCP showed the uptake of taurocholate to be rapid and predominantly sodium dependent (Fig. 2). The derived Km value of 7.9 ± 2.0 μM for taurocholate uptake is in close agreement to theKm value of 6.2 μM ...
Effects of NR1I2 TGT and CYP2B6*6 on induction of bupropion hydroxylation by SF.Individual profiles showing AUC_hyd/AUC_bup ratios for the basal and SF-induced
Recent studies have revealed that about half of the variations seen in patients taking the anticoagulant warfarin are due to PGx factors. The consequences of incorrect warfarin dosing are obviously serious, with inadequate doses predisposing patients to thrombosis and higher doses placing them at risk for hemorrhage ...
Способность ферментов биотрансформации ксенобиотиков опухолевой клетки метаболизировать цитостатики может влиять на чувствительность опухоли к химиотерапии и, как следствие, на исход лечения. В биотрансформации препаратов, входящих в стандартные протоколы неоадъювантной химиотерапии, участвуют ферменты суперсемейства цитохромов Р450 (CYP), функциональные свойства которых могут зависеть от уровня экспрессии их генов. В работе определен уровень экспрессии генов цитохромов CYP1В1, CYP2А6, CYP3A4, CYP3A5, CYP2B6, CYP2C8, CYP2C9, CYP2C19 в 62 образцах опухолевой ткани у ...
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View mouse Cyp2r1 Chr7:114549682-114562972 with: phenotypes, sequences, polymorphisms, proteins, references, function, expression
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HEK293T cells were transfected with the pCMV6-ENTRY control (Left lane) or pCMV6-ENTRY CYP17A1 (RC209042, Right lane) cDNA for 48 hrs and lysed. Equivalent amounts of cell lysates (5 ug per lane) were separated by SDS-PAGE and immunoblotted with anti-CYP17A1 ...
You may need close monitoring or dosing adjustments if you combine certain medications with Rythmol SR. This eMedTV Web article explores a number of important drug interactions that may occur with Rythmol SR and how to reduce your risk for problems.
豊田茂 厚生科学研究班「小児等特殊患者群に対する医薬品の用法 用量の確立に関する研究」平成14年度報告書, 2002 被引用文献1件 ...
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Introduction: Because of the unique lack of genetic diversity despite the multiethnicity in the Asian population, we hypothesize that single-nucleotide polymorphisms in cytochrome P450 (CYP) 2C9 (CYP2C9*3) and vitamin K epoxide reductase complex subunit 1 (VKORC1) at position 381, used to infer VKORC1haplotype in combination with demographic factors, can accurately predict warfarin doses. The aims of this study were to derive a pharmacogenetics-based dosing algorithm by use of retrospective information and to validate it through a data-splitting method in a separate cohort of equal size. Methods: We used 215 records of warfarin patients recruited into a CYP2C9/VKORC1 genotyping study to perform this analysis. Univariate analyses for individual predictors, including age, weight, gender, serum albumin concentration, ethnic group, international normalized ratio, and CYP2C9 and VKORC1 381 genotypes, were conducted to select variables with P < .1 for further inclusion into the multivariate ...
BACKGROUND Primary congenital glaucoma generally presents with a classic clinical triad of photophobia, blepharospasm, and epiphora caused by the corneal changes that occur secondary to increased intraocular pressure (IOP). The condition typically presents bilaterally and is rarely hereditary. Onset is from age 2 months to 2 to 3 years. CASE REPORT A 2-year, 5-month-old Hispanic boy presented with an enlarged right eye and an intermittent right exotropia, without tearing or photophobia. Examination also found high myopia and an optic nerve cup-to-disc ratio larger in the right than the left eye. Referral to a pediatric ophthalmologist was initiated. On the first examination under anesthesia (EUA), the child was diagnosed with unilateral megalocornea with a normal IOP. He did not have any other typical signs and symptoms of primary congenital glaucoma. An EUA 8 months later led to a diagnosis of primary congenital glaucoma based on the new appearance of Haabs striae, further enlargement of the cornea,
1. We have constructed a full-length human liver cytochrome P450IIA cDNA from a partial-length clone by oligonucleotide-directed mutagenesis, and subcloned it into the monkey kidney (COS-7) cell expression vector, pSVL. 2. The cDNA encodes a 49 kDa protein with coumarin 7-hydroxylase (COH) activity which cross-reacts with antisera to the mouse cytochrome P-450 isoenzyme responsible for COH activity and comigrates with a human liver microsomal protein. 3. Western blot analysis of a panel of human livers indicates that the level of the 49 kDa protein, detected using antisera to either the mouse COH P-450 or rat P450IIA1 protein, correlates very highly with COH activity. 4. Antisera to the rat P450IIA1 protein can inhibit COH activity in human liver microsomes. Taken together, these data indicate that a member of the P450IIA subfamily is responsible for most, if not all, of the COH activity in human liver. ...
VKORC1 overexpression lysate, 0.1 mg. Transient overexpression lysate of vitamin K epoxide reductase complex, subunit 1 (VKORC1), transcript variant 1
DISCUSSION. Previous reports3,4,5,6illustrate the influence of isolated risk factors on high warfarin dose requirements. None of these reports demonstrated the synergistic influence of multiple risk factors resulting in higher doses or multiple adjustments in multivariate analysis.. In regards to drug-drug interaction, phenobarbital could have contributed with the highest warfarin dose ever reported, since it is known the drug interaction on CYP as enzyme inhibitor mechanisms.3 Paradoxically, the use of corticosteroids could contribute to lower warfarin dose requirements to achieve therapeutic INR levels, as previously seen in patients with CYP2C9 polymorphisms.7 However, in the present case, the use of prednisone and dose tapering strategy did not significantly affect INR and warfarin dose changes (Figure 1).. The striking risk factors for higher warfarin doses were age and enteral tube feeding. Age-related factors, such as infants3 need higher doses of warfarin (~0.3 mg/kg) than older children ...
The cytochrome P450 (CYP) enzyme superfamily is involved in phase I metabolism which chemically modifies a variety of substrates via oxidative reactions to make them more water-soluble and easier to eliminate. Inhibition of these enzymes leads to undesirable effects, including toxic drug accumulations and adverse drug-drug interactions. Hence, it is necessary to develop in silico models that can predict the inhibition potential of compounds for different CYP isoforms. This study focused on five major CYP isoforms, including CYP1A2, 2C9, 2C19, 2D6 and 3A4, that are responsible for more than 90% of the metabolism of clinical drugs. The main aim of this study is to develop a multiple-category classification model (MCM) for the major CYP isoforms using a Laplacian-modified naive Bayesian method. The dataset composed of more than 4500 compounds was collected from the PubChem Bioassay database. VolSurf+ descriptors and FCFP_8 fingerprint were used as input features to build classification models. The ...
Mechanism-based inhibition of cytochrome P450 involves the bioactivation of the drug to a reactive metabolite, which leads to cytochrome inhibition via various mechanisms. This is ..
Interindividual variations in the level and activity of cytochrome P-450 enzymes were investigated in the liver microsomes of 30 Japanese and 30 Caucasian patients. The P-450 enzymes used in this study included P-450 1A2, 2A6, 2B6, 2C, 2D6, 2E1 and 3A, and the monooxygenase activities determined were 13 typical P-450 substrates and 9 procarcinogens. Although the total P-450 content was higher in Caucasian (mean, 0.43 nmol/mg of protein) than in Japanese populations (mean, 0.26 nmol/mg of protein), the relative levels (percent of total P-450) of individual forms of P-450 determined immunochemically were not very different except that P-450 2A6 and 2B6 levels were higher in the Caucasians. About 70% of liver P-450 could be accounted for by P-450 1A2, 2A6, 2B6, 2C, 2D6, 2E1 and 3A proteins, and P-450 3A (about 30% of total P-450) and 2C (about 20%) enzymes were found to be the major forms. Considerable levels of P-450 1A2 (about 13%) and 2E1 (about 7%) could be determined, whereas the P-450 2A6 ...
Almost one half of prospective drugs, including new chemical entities are not suitable for clinical use because of their metabolic unstability and for danger of drug interactions. This type of toxicity has been underlying several drug withdrawals in recent years and hence it is needed now to bring with any new compound proposed an information on its metabolism and on its interactions with major drug metabolizing enzyme systems namely with liver microsomal cytochromes P450 (CYP). Then, possibility of drug interactions with other drugs taken by the patient on the basis of drug metabolism may be evaluated to prevent significant losses in time, effort and money in drug development. The analysis of drug metabolism by individual CYPs, the possibility of drug interactions and of induction of individual CYP forms are performed with CYP in vitro systems with the respective substrates, inhibitors and inductors based on the recommendation of the U.S. Food and Drug Administration: ...
Warfarin has been in clinical use for nearly 60 years, and in 2010 there were ,25 million prescriptions for warfarin in the United States. Although warfarin is highly efficacious, it has a narrow therapeutic window to achieve desired anticoagulation without excess risk of bleeding. Anticoagulation status is monitored with the International Normalized Ratio (INR), where the most common target INR is 2 to 3. Not only does warfarin exhibit a narrow therapeutic index, but there can be 10- to 20-fold differences in the warfarin dose required to achieve target INR. Thus, the early period after warfarin therapy initiation requires frequent INR monitoring to determine the proper dose for the patient, it is often associated with multiple dose adjustments, and many patients experience prolonged periods of over- or underanticoagulation while the appropriate dose is identified. These challenges lead to warfarin being a leading cause of emergency department visits and hospitalizations for an adverse drug ...
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CYP4F (Cytochrome P4504F) enzymes metabolize endogenous molecules including leukotrienes, prostaglandins and arachidonic acid. The involvement of these endogenous compounds in inflammation has led to the hypothesis that changes in the inflamed tissue environment may affect the expression of CYP4Fs during the pro-inflammatory state, which in turn may modulate inflammatory conditions during the anti-inflammatory state. We demonstrated that inflamed tissues have different levels of CYP4F isoform expression profiles in a number of human samples when compared to the average population. The CYP4F isoform expression levels change with the degree of inflammation present in tissue. Further investigation in cell culture studies revealed that inflammatory cytokines, in particular TNF-α, play a role in regulating the expression of the CYP4F family. One of the isoforms, CYP4F11, had different characteristics than that of the other five CYP4F family members. CYP4F11 metabolizes xenobiotics while the other isoforms
Backup that can be transported offsite is what you need, paxil cost not replica! The patient does not feel well in general and has had a low-grade fever of around 100°F (38°C). A reduction in starting dose is recommended for patients who are CYP2D6 intermediate metabolizers and CYP2C19 poor metabolizers. Discounted flat-rate shipping of $12 USD for Canadian orders of $100 USD or more ($1750 USD shipping for orders below $100 USD)? W zależności od producenta lek jest dostępny w dawkach: 2, paxil cost5 mg, 5 mg, 10 mg i 20 mg. Ly speaking its not considered safe to use oregano oil during pregnancy. The method of claim 16, paxil cost wherein the formulation is further administered in combination with an agent selected from the group consisting of beta blockers, aspirin, and thrombolytics? Les noms et logotypes propriétés de Pfizer et notamment les noms et logotypes éventuellement associés au Site constituent des marques déposées et protégées? Call your doctor for medical advice about ...
With regards to nicotine metabolism, 2 genes appear to stand out in particular: CYP2A6 and CYP2B6 (note the similarity in nomenclature between these and the gene/enzyme mentioned above for Strattera metabolism CYP2D6. This is not an accident, as all three of these belong to the same "superfamily" of enzymes and carry many similar chemical and functional similarities). Out of these, the CYP2A6 (hereafter abbreviated as "2A6") enzyme is responsible for the lions share of nicotine metabolism. It is coded for by by a gene of the same name, located in the "q13.2" region on the 19th human chromosome. Like the 2D6 gene for Strattera, the 2A6 gene can exist in multiple different forms. Some 2A6 gene forms produce higher levels of the 2A6 enzyme than others. Other forms of 2A6 are less efficient, which results in a slower breakdown and clearance of nicotine. As a result, the nicotine stays in the body longer, and less of it is typically required. As a result individuals with these less efficient forms ...
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in this discovery process is to identify drug-drug supernatant were dissolved with four (4) volume of interactions. The most widespread procedure for this acetonitrile and 2µL were transferred to a 96-well is to perform cytochrome P450 (CYP) inhibition assays LazWell plate. The solvent was evaporated to dryness using human liver microsomes (HLM). The most at room temperature. This dilution step was necessary commonly used method for analyzing CYP inhibition to reduce the unvolatile content into the final dry assay samples is LC-MS/MS. However, this method is samples. The resulting dry samples were analyzed in time-consuming and represents the bottleneck in this LDTD-MS/MS. Labelled internal standard were used type of assay. To increase the throughput, we propose for OH-midazolam and OH-diclofenac only. Table 1 Incubation conditions of the CYP assay ...
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Approximately 7-10% of people are poor metabolizers of the popular anticoagulant Warfarin and would probably need a decreased dosage. This due to mutations in rs1799853 or rs1057910 causing an inactive CYP2C9 gene. You are at increased risk of drug-induced side effects due to diminished drug elimination. Prodrugs dependent on CYP2C9 metabolism may fail to generate the active form of the drug. ...
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... are used to help predict how an individual will respond to a particular medication. Some people respond differently to a drug than other people do; for example, they may metabolize the drug too quickly or too slowly or not at all - meaning that the drug may not be effective or it may remain in a persons system too long and lead to side effects.
Product Name: 1,8-DibromonaphtaleneFormula: C10H6Br2Weight: 285.96264SMILES: BrC1C2C(C=CC=1)=CC=CC=2BrCAS NO: 1137868-96-2 Product: TAK-960 (hydrochloride)
Product Name: 2-TriphenylenecarbaldehydeFormula: C19H14OWeight: 258.31386SMILES: O=CC1C=C2C(=CC=1)C3C(C=CCC=3)=C4C2=CCC=C4CAS NO: 1609960-31-7 Product: TH588
Warfarin is an oral anticoagulant used for prevention of thromboembolism in children. Its dosing is difficult due to the narrow therapeutic index & individual variability in effective dosage. Genetic polymorphism in 2 enzymes involved in warfarin metabolism, vitamin K epoxide reductase (VKORC) & cytochrome P450 isoenzyme 2C9 (CYP2C9), have been associated with lower dose requirements in adults. Testing for these polymorphisms is now recommended and being performed to guide dosing in adult patients(pts). Currently there is no information available on these polymorphisms & warfarin dosing in children. To examine the relationship between warfarin dosing & polymorphisms of CYP2C9 & VKORC1 in pediatric patients. Pts 0 -18 years old on warfarin for minimum 2 weeks were included. Data included ethnicity, age, weight, body surface area, gender, indication, dose, INR, target INR, medical illness or medications & adverse effects. Blood sample tested for CYP2C9 & VKORC1 genotypes & correlated with above ...
The constitutive androstane receptor (CAR) also known as nuclear receptor subfamily 1, group I, member 3 is a protein that in humans is encoded by the NR1I3 gene. CAR is a member of the nuclear receptor superfamily and along with pregnane X receptor (PXR) functions as a sensor of endobiotic and xenobiotic substances. In response, expression of proteins responsible for the metabolism and excretion of these substances is upregulated. Hence, CAR and PXR play a major role in the detoxification of foreign substances such as drugs. Androstenol and several isomers of androstanol, androstanes, are endogenous antagonists of the CAR, and despite acting as antagonists, were the basis for the naming of this receptor. More recently, dehydroepiandrosterone (DHEA), also an androstane, has been found to be an endogenous agonist of the CAR. CAR is a member of the nuclear receptor superfamily, and is a key regulator of xenobiotic and endobiotic metabolism. Unlike most nuclear receptors, this transcriptional ...
Hypothesis: We hypothesize that warfarin dose requirement could be more accurately predicted using a simplified genotyping procedure requiring the identification of a single CYP2C9 allele and a single nucleotide polymorphism of VKORC1 to discern between the 2 major haplotypes H1 and H7.. Aims: The aim is to compare the clinical benefits of genetics-guided dosing versus traditional trial and error dosing with protocol guided-adjustments. Two secondary objectives are (1) to prospectively evaluate a dosing algorithm built on demographics and genetic predictors; (2) to assess the feasibility of a simplified test for CYP2C9*3 and VKORC1 SNP in clinical practice.. Methodology: A randomized controlled trial targeted at accruing 100 patients with indication for wafarin therapy. The endpoint for comparing genetics-guided dosing against traditional dosing method at the anticoagulant clinic is the number of dosage titrations to achieve targeted International Normalized Ratio (INR) at 1, 2 and 3 months of ...
In the obersvation of " Evidence for the involvement of human liver microsomes CYP1A2 in the mono-hydroxylation of daidzein" by Peng WX, Wang LS, Li HD, Abd El-Aty AM, Chen GL, Zhou HH., posted in US National Library of Medicine National Institutes of Health, researchers found that Michaelis-Menten kinetic parameters were best fitted to a one-component enzyme kinetic model. The mean K(m) (micromol/l) and V(max) (micromol/g min) values (+/-S.D.) were 26.86 (10.45) and 4.76 (2.07), 53.83 (22.25) and 2.29 (1.04), 51.48 (29.32) and 2.21(0.82), for the formation rates of 7,8,4-THI, 7,3,4-THI and 6,7,4-THI, respectively. Furafylline, the CYP1A2-specific inhibitor, estrogen and monoclonal antibody raised against human CYP1A2 (MAB-1A2) substantially inhibited the formation rates of mono-hydroxylated metabolites. The IC(50) of Fur for the formation of 7,3,4-THI, 6,7,4-THI and 7,8,4-THI was 1.0, 0.9 and 0.8 micromol/l, respectively. The IC(50) of estrogen for the formation of 7,3,4-THI, ...
The cytochrome P450 (CYP) family is involved in the primary metabolism of many drugs. The CYPs are a group of oxidative/dealkylating enzymes localized in the microsomes of many tissues including the intestines and liver. One of these CYP enzymes, CYP1A2, is wholly or partially responsible for the hydroxylation or dealkylation of many commonly prescribed drugs.. CYP1A2-mediated drug metabolism is highly variable. A number of variants have been identified in the CYP1A2 gene that results in increased, diminished, or abolished catalytic activity and substrate metabolism. The frequency of these variants varies by ethnicity.. Dosing of drugs that are metabolized through CYP1A2 may require adjustment based on the CYP1A2 genotype. Individuals who are poor metabolizers may require lower than usual doses to achieve optimal response, whereas individuals who are ultrarapid metabolizers may benefit from increased doses. CYP1A2 phenotype is predicted based upon the number of functional, partially functional, ...
... , Authors: Sayka Barry, Márta Korbonits. Published in: Atlas Genet Cytogenet Oncol Haematol.
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Many antidepressant drugs are metabolized, or processed, by two enzymes called CYP2D6 and CYP2C19. Drugs used to treat psychosis (antipsychotics) and Strattera® (generic name atomoxetine), an attention deficit with hyperactivity disorder (ADHD) drug, are also metabolized by the CYP2D6 enzyme. Changes in the genes that make these enzymes can cause you to metabolize drugs in an unexpected way. Th way people respond to the same antidepressant or antipsychotic drug and dose varies a lot. Changes in certain genes may change the response to a drug. Genetic testing can look for common changes in the CYP2D6 and CYP2C19 genes to find people who metabolize certain drugs faster or slower than usual. If you metabolize faster, you are called an Ultrarapid Metabolizer. If you metabolize more slowly, you are called a Poor Metabolizer. People who metabolize a little more slowly than usual are called Intermediate Metabolizers. Sometimes this information can be used by your doctor to predict if you are ...
But not everyone has exactly the same version a CYP2A6 gene. In fact, some do not have the gene at all. In a second study of 200 light and 200 heavy smokers, Tyndale and Sellers found that those with slight variations in their CYP2A6 gene smoked about six fewer cigarettes per day and had lower carbon monoxide levels in their breath a measure of smoking exposure. These different versions of the gene confer protection upon the smoker by processing nicotine less efficiently.. Having certain mutant versions of the CYP2A6 gene or not having the CYP2A6 gene at all is quite beneficial, says Sellers. People lacking the CYP2A6 are less likely to become addicted to nicotine. On the other hand, people with more than two copies of the common CYP2A6 gene are susceptible to smoking heavily because they will process nicotine faster, and will need to smoke more to satisfy their addiction.. Another speaker at the conference, Neal Benowitz, of the University of California, San Francisco, presented work that ...
In the current study, the relationships between various polymorphisms of two CYP450 enzymes (CYP2C9 and CYP2C19) and the pharmacokinetics of indisulam were assessed. It was shown that the elimination rate of indisulam was significantly decreased by CYP2C9*3, CYP2C19*2, and CYP2C19*3 polymorphisms. These CYP2C mutations caused an increased risk of dose-limiting neutropenia.. The activity of the *3-mutated CYP2C9 enzyme was shown to be reduced for S-warfarin in vitro by Haining et al. (33). This polymorphism was also associated to poor tolbutamide metabolism in vivo (34). In the current pharmacogenetic study, the *3 mutation in the CYP2C9 gene reduced the Michaelis-Menten elimination rate of indisulam. Thus, the saturable elimination pathway may correspond to hydroxylation of indisulam by CYP2C9 (19).. De Morais et al. (23, 24) showed that the *2 and *3 mutations in the CYP2C19 gene created a premature stop codon, resulting in a truncated nonfunctional CYP2C19 protein. These CYP2C19 mutations were ...
The aim of this study was to assess the pharmacokinetics and pharmacodynamics of warfarin associated with genetic polymor phisms in VKORC1, CYP2C9, CYP2C19, and CYP4F2 in Indonesian patients treated w
Coumarins are widely prescribed worldwide, and in Mexico acenocumarol is the preferred form. It is well known that despite its efficacy, coumarins show a high variability for dose requirements. We investigated the pharmacogenetic variation of 110 genes in patients receiving acenocumarol using a targeted NGS approach. We report relevant population differentiation for variants on CYP2C8, CYP2C19, CYP4F11, CYP4F2, PROS, and GGCX, VKORC1, CYP2C18, NQO1. A higher proportion of novel-to-known variants for 10 genes was identified on 41 core pharmacogenomics genes related to the PK (29), PD (3), of coumarins, and coagulation proteins (9) including, CYP1A1, CYP3A4, CYP3A5, and F8, and a low proportion of novel-to-known variants on CYP2E1, VKORC1, and SULT1A1/2 ...
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Learn about the CYP2C9 and VKORC1 pharmacogenomic tests that predict how your genes will affect your bodys response to warfarin (Coumadin, Jantoven).
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The oral anticoagulant acenocoumarol is given as a racemic mixture. The (S)-enantiomer is rapidly cleared and is the reason why only (R)-acenocoumarol contributes to the pharmacological effect. The objective of the study was to establish the cytochrome P450 (CYP) enzymes catalyzing the hydroxylations of the acenocoumarol enantiomers. Of various cDNA-expressed human CYPs, only CYP2C9 hydroxylated (S)-acenocoumarol. Hydroxylation occurred at the 6-, 7-, and 8-position with equal Km values and a ratio of 0.9:1:0.1 for Vmax. CYP2C9 also mediated the 6-, 7-, and 8-hydroxylations of (R)-acenocoumarol with Km values three to four times and Vmax values one-sixth times those of (S)-acenocoumarol. (R)Acenocoumarol was also metabolized by CYP1A2 (6-hydroxylation) and CYP2C19 (6-, 7-, and 8-hydroxylation). In human liver microsomes one enzyme only catalyzed (S)-acenocoumarol hydroxylations with Km values | 1 mM. In most of the samples tested the 7-hydroxylation of (R)-acenocoumarol was also catalyzed by one enzyme
Aryl hydrocarbon hydroxylase (AHH) was induced 15-fold in Ambystoma tigrinum by intraperitoneal injection of 3-methylcholanthrene in corn oil, or 10-fold by addition of aromatic polycyclic hydrocarbons to the aqueous environment of the neotene animal. The cytochrome P-450-associated microsomal enzyme is similar to the inducible, one-gene, autosomal-dominant system typical in the laboratory mouse and man. Differences in optimal temperature for enzyme induction and activity were noted in organ culture of human and Ambystoma tissues, and ratios of benzpyrene metabolites differed between Ambystoma and Mus. The half life of enzyme activity induced in vivo was related to the excretion of hydrocarbon metabolites.
Pharmacogenetics is a branch of science that studies the association of genotype with individual response to drug therapy. The potential of pharmacogenetics is great because further research will enable and facilitate individualized treatment of some diseases. Tiopurin S-methyltransferase (TPMT) is an enzyme that inactivates thiopurine drugs and prevents their transformation to toxic products. The TPMT gene exhibits genetic polymorphisms that cause variable enzyme activity. TPMT deficient patients are at high risk of hematologic toxicity and should be treated with reduced dose of thiopurine drugs. Four polymorphic variant TPMT alleles have been most studied because they have the greatest impact on reducing activity of TPMT: TPMT*2, TPMT*3A, TPMT*3B and TPMT*3C. Warfarin, an anticoagulant, acts as an antagonist of vitamin K epoxide reductase complex (VKORC1 subunit). Polymorphisms in CYP2C9 (metabolizes Warfarin) and VKORC1 cause variable patient response. The most common variant alleles for ...
retinoic acid hydroxylase. 3 subfamilies, 3 genes. CYP26A1, CYP26B1, CYP26C1 CYP27. varied. 3 subfamilies, 3 genes. CYP27A1 ( ... Oxygen rebound mechanism utilized by cytochrome P450 for conversion of hydrocarbons to alcohols via the action of "compound I ... Clozapine, imipramine, paracetamol, phenacetin Heterocyclic aryl amines Inducible and CYP1A2 5-10% deficient oxidize ... cholesterol 24-hydroxylase. 1 subfamily, 1 gene. CYP46A1 CYP51. cholesterol biosynthesis. 1 subfamily, 1 gene, 3 pseudogenes. ...
This enzyme is responsible in part for the reductive dearomatization of aryl compounds mediated by bacteria under anaerobic ... This intermediate is subsequently converted by a benzophenone 3′-hydroxylase, a cytochrome P450 monooxygenase, leading to the ... "Anaerobic oxidation of aromatic compounds and hydrocarbons" Current Opinion in Chemical Biology 2002 Volume 6, pp. 604-611. doi ...
... aryl-4-monooxygenase, aryl hydrocarbon hydroxylase, microsomal P-450, flavoprotein-linked monooxygenase, and flavoprotein ... Mitoma C, Udenfriend S (1962). "Aryl-4-hydroxylase". Methods Enzymol. 5: 816-819. doi:10.1016/s0076-6879(62)05318-5. Napoli JL ... Nebert DW, Gelboin HV (1968). "Substrate-inducible microsomal aryl hydroxylase in mammalian cell culture. I. Assay and ...
... and the aryl hydrocarbon receptor nuclear translocator (Arnt), the beta subunit. HIF1A contains a basic helix-loop-helix domain ... In normal circumstances after injury HIF-1a is degraded by prolyl hydroxylases (PHDs). In June 2015, scientists found that the ... In addition, the coordinated activity of the prolyl hydroxylases (PHDs) maintain the appropriate balance of HIF1A protein in ... Bruick RK, McKnight SL (Nov 2001). "A conserved family of prolyl-4-hydroxylases that modify HIF". Science. 294 (5545): 1337-40 ...
Exposure to o-toluidine enhances the microsomal activity of aryl hydrocarbon hydroxylase (particularly in the kidney), NAPDH- ...
... steroid 20α-hydroxylase, steroid 22-hydroxylase, cholesterol side-chain scission). CYP11B1 (encoding the protein P450c11β) ... are inducible by some polycyclic hydrocarbons, some of which are found in cigarette smoke and charred food. These enzymes are ... phenacetin Heterocyclic aryl amines Inducible and CYP1A2 5-10% deficient oxidize uroporphyrinogen to uroporphyrin (CYP1A2) in ... found in the inner mitochondrial membrane of adrenal cortex has steroid 11β-hydroxylase, steroid 18-hydroxylase, and steroid 18 ...
CYP1A1 is also known as AHH (aryl hydrocarbon hydroxylase). It is involved in the metabolic activation of aromatic hydrocarbons ... Kiyohara C, Hirohata T, Inutsuka S (Jan 1996). "The relationship between aryl hydrocarbon hydroxylase and polymorphisms of the ... and the aryl hydrocarbon receptor nuclear translocator. In the intestine, but not the liver, CYP1A1 expression moreover depends ... is regulated by a heterodimeric transcription factor that consist of the aryl hydrocarbon receptor, a ligand activated ...
... aryl hydrocarbon hydroxylases MeSH D08.244.453.040.050 --- aniline hydroxylase MeSH D08.244.453.040.110 --- benzopyrene ... aryl hydrocarbon hydroxylases MeSH D08.811.682.690.708.170.040.024 --- 7-alkoxycoumarin o-dealkylase MeSH D08.811.682.690. ... steroid 11-beta-hydroxylase MeSH D08.811.682.690.708.170.915.730 --- steroid 12-alpha-hydroxylase MeSH D08.811.682.690.708.170. ... steroid 11-beta-hydroxylase MeSH D08.244.453.915.730 --- steroid 12-alpha-hydroxylase MeSH D08.244.453.915.737 --- steroid 16- ...
Nguyen NT, Kimura A, Nakahama T, Chinen I, Masuda K, Nohara K, Fujii-Kuriyama Y, Kishimoto T (2010). "Aryl hydrocarbon receptor ... Kynurenine 3-hydroxylase converts kynurenine to 3-hydroxykynurenine. Dysfunctional states of distinct steps of the kynurenine ... "An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor". Nature. 478 (7368): 197-203. doi:10.1038/ ...
... aryl hydrocarbon hydroxylases MeSH D12.776.422.220.453.040.050 - aniline hydroxylase MeSH D12.776.422.220.453.040.110 - ... steroid 11-beta-hydroxylase MeSH D12.776.422.220.453.915.730 - steroid 12-alpha-hydroxylase MeSH D12.776.422.220.453.915.737 - ... steroid 16-alpha-hydroxylase MeSH D12.776.422.220.453.915.748 - steroid 17-alpha-hydroxylase MeSH D12.776.422.220.453.915.760 ... cholesterol 7 alpha-hydroxylase MeSH D12.776.422.220.453.915.212 - cholesterol side-chain cleavage enzyme MeSH D12.776.422.220. ...
In addition to its antiandrogenic activity, flutamide has been identified as a putative ligand of the aryl hydrocarbon receptor ... Flutamide and hydroxyflutamide have been found in vitro to inhibit CYP17A1 (17α-hydroxylase/17,20-lyase), an enzyme which is ... "Anti-androgen flutamide suppresses hepatocellular carcinoma cell proliferation via the aryl hydrocarbon receptor mediated ... Ayub, M.; Levell, M.J. (1987). "Inhibition of rat testicular 17α-hydroxylase and 17,20-lyase activities by anti-androgens ( ...
1990) compared the effects of fetal versus adult exposure to 3-MC on both induction of aryl hydrocarbon hydroxylase (AHH) ... 3-MC is a ligand of the aryl hydrocarbon receptor (AhR), which stimulates transcription directed by xenobiotic response ... Shipley, J. M.; Waxman, D.J. (2006). "Aryl hydrocarbon receptor-independent activation of estrogen receptor-dependent ... This is likely because it is plausible that two polycyclic aromatic hydrocarbons are metabolized via the same pathway. ...
... the latter being a constitutively-expressed aryl hydrocarbon receptor nuclear translocator (ARNT). HIF-1 belongs to the PER- ... By inhibiting prolyl-hydroxylase enzyme, the stability of HIF-2α in the kidney is increased, which results in an increase in ... In normal circumstances after injury HIF-1a is degraded by prolyl hydroxylases (PHDs). In June 2015, scientists found that the ... Maxwell PH, Eckardt KU (March 2016). "HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond". Nature ...
Aryl hydrocarbon hydroxylase activity in the fungus Cunninghamella bainieri: Evidence for the presence of cytochrome P-450. J.P ... Many species are also capable of oxidizing polycyclic aromatic hydrocarbons, a class of stable organic molecules that tends to ... Cerniglia, Carl E. (1992). "Biodegradation of polycyclic aromatic hydrocarbons". Biodegradation. 3 (2-3): 351-368. doi:10.1007/ ...
... aryl hydrocarbon hydroxylase (AHH), ethylmorphine N-demethylase, Uridine diphosphate (UDP) glucuronyltransferase (UGT), P- ...
Metabolism Aryl-alcohol dehydrogenase uses an aromatic alcohol and NAD+ to produce an aromatic aldehyde, NADH and H+. Aryl- ... In Sorghum, the SbF3'H2 gene, encoding a flavonoid 3'-hydroxylase, seems to be expressed in pathogen-specific 3- ... bonded directly to an aromatic hydrocarbon group. The simplest of the class is phenol, which is also called carbolic acid C 6H ... uses an aryl dialkyl phosphate and H2O to produce dialkyl phosphate and an aryl alcohol. Gyrophoric acid, a depside, and ...
A. Jaworski; L. Sedlaczek; J. Dlugoński; Ewa Zajaczkowska (1985). "Inducible nature of the steroid 11-hydroxylases in spores of ... Cytochrome P450 monooxygenase, aryl sulfotransferase, glutathione S-transferase, UDP-glucuronosyltransferase, UDP- ... elegans has been implicated in the neutralization of numerous polycyclic aromatic hydrocarbons (PAH). It can degrade molecules ...
... basal activities and inducibility of epoxide hydrolases and aryl hydrocarbon hydroxylase". Biochem. Pharmacol. 33 (1): 71-7. ... Casson AG, Zheng Z, Porter GA, Guernsey DL (2006). "Genetic polymorphisms of microsomal epoxide hydroxylase and glutathione S- ... but more complex compounds as polycyclic aromatic hydrocarbons are rather bioactivated to genotoxic species. EPHX1 mediates the ... "Stereoselective epoxidation and hydration at the K-region of polycyclic aromatic hydrocarbons by cDNA-expressed cytochromes ...
... uses an aryl dialkyl phosphate and H2O to produce dialkyl phosphate and an aryl alcohol. ... Shih, C. -H.; Chu, I. K.; Yip, W. K.; Lo, C. (2006). "Differential Expression of Two Flavonoid 3'-Hydroxylase cDNAs Involved in ... bonded directly to an aromatic hydrocarbon group. The simplest of the class is phenol, which is also called carbolic acid C. 6H ... Aryl-alcohol dehydrogenase (NADP+) uses an aromatic alcohol and NADP+ to produce an aromatic aldehyde, NADPH and H+. ...
aryl hydrocarbon receptor nuclear translocator 2. 0.013. Plcd4. phospholipase C, delta 4. 0.013. ... dopamine beta-hydroxylase (dopamine beta-monooxygenase). 0.011. Gfra1. GDNF family receptor alpha 1. 0.011. ...
Aryl Hydrocarbon Hydroxylases / genetics* * Aryl Hydrocarbon Hydroxylases / metabolism * Clopidogrel * Cytochrome P-450 CYP2C19 ...
Aryl hydrocarbon Receptor (AhR). *c-Fos/AP-1. *c-Myc. *CREB/CBP ... HIF/HIF Prolyl-hydroxylase. *IRE1. *Keap1-Nrf2. *Kruppel-like ...
Aryl Hydrocarbon Receptors. *Constitutive Androstane Receptor. *Estrogen Receptors. *Glucocorticoid Receptors. *LXR-like ...
Aryl Hydrocarbon Receptors. *Constitutive Androstane Receptor. *Estrogen Receptors. *Glucocorticoid Receptors. *LXR-like ...
Vorrink, S. U., Severson, P. L., Kulak, M. V., Futscher, B. W. & Domann, F. E. (2014). Hypoxia perturbs aryl hydrocarbon ... Place, T. L., Nauseef, J. T., Peterson, M. K., Henry, M. D., Mezhir, J. J. & Domann, F. E. (2013). Prolyl-4-hydroxylase 3 (PHD3 ... Xiao, W., Son, J., Vorrink, S. U., Domann, F. E. & Goswami, P. C. (2015). Ligand-independentactivation of aryl hydrocarbon ... Vorrink, S. U., Hudachek, D. R. & Domann, F. E. (2014). Epigenetic determinants of CYP1A1induction by the aryl hydrocarbon ...
Synergistic induction of aryl hydrocarbon hydroxylase (AHH) activity in human fetal hepatocytes by polycyclic hydrocarbons and ...
Aryl hydrocarbon Receptor (AhR). *c-Fos/AP-1. *c-Myc. *CREB/CBP ... HIF/HIF Prolyl-hydroxylase. *IRE1. *Keap1-Nrf2. *Kruppel-like ...
acid, but the perpendicular may now be writers on classical aryl and on the current food. small to the biological management of ... water is how Franklin was one of the greatest Regulated announcements of his hydroxylase, the routinely radial P4Hs of ... Penicillium and is a Many hydrocarbon; control. effectiveness of processing sensations, patient as variables and steeple pigs, ...
Aryl Hydrocarbon Receptor. *Salt-inducible Kinase (SIK). *SPHK. *STING. *STING. *JAK/STAT*EGFR ... Tryptophan hydroxylase. *Xanthine oxidase. *Metabolic Enzyme/Protease*Aldehyde Dehydrogenase (ALDH). *Adenosine Deaminase ...
aryl hydrocarbon receptor nuclear translocator-like. 0.062. Epas1. endothelial PAS domain protein 1. 0.058. ... dopamine beta hydroxylase. 0.016. Elf4. E74-like factor 4 (ets domain transcription factor). 0.015. ...
Non-hypoxic transcriptional activation of the aryl hydrocarbon receptor nuclear translocator in concert with a novel hypoxia- ... The cellular levels of HIF-1 in the cell depend on many factors, such as distribution of hydroxylases that take part in ... the β subunit is produced in most tissues and is also known as aryl hydrocarbon receptor nuclear translocator (ARNT). Besides ... The oxygen level gradient formed as a certain distance from the vessel affects the activity of hydroxylases. At sites of low ...
Optimization of 3-aryl-3-ethoxypropanoic acids and discovery of the potent GPR40 agonist DS-1558, Bioorganic & Medicinal ... Raman spectra and DFT calculations for tetraterpene hydrocarbons from the L race of the green microalga Botryococcus braunii, ... Integrating an algal β-carotene hydroxylase gene into a designed carotenoid-biosynthesis pathway increases carotenoid ... Raman spectra and DFT calculations for botryococcene and methylsqualene hydrocarbons from the B race of the green microalga ...
... also called Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT), to regulate gene expressions [7]. HIF downstream target ... Regulation of cellular levels of Sprouty2 protein by prolyl hydroxylase domain and von Hippel-Lindau proteins. J Biol Chem. ... The von Hippel-Lindau tumor suppressor protein and Egl-9-Type proline hydroxylases regulate the large subunit of RNA polymerase ... two key proline residues in the oxygen-dependent degradation domain of HIFα were hydroxylated by HIF prolyl hydroxylases (PHD1- ...
The hydroxylase cytochrome P450 1A1 (CYP1A1) is regulated by the inflammation-limiting aryl hydrocarbon receptor (AhR), but ...
Trace derivatives of kynurenine potently activate the aryl hydrocarbon receptor (AHR). J. Biol. Chem. 2018, 293, 1994-2005. [ ... A full kinetic model would also include rate laws for IDO2, for tryptophan hydroxylase (TPH1 or TPH2 depending on the cell type ... Walther, D.J.; Bader, M. A unique central tryptophan hydroxylase isoform. Biochem. Pharmacol. 2003, 66, 1673-1680. [Google ... As an example, tyrosine hydroxylase, the first and rate-determining step in dopamine synthesis, is also substrate inhibited and ...
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... also called the aryl hydrocarbon receptor nuclear translocator) (21). Under hypoxic conditions, HIFα accumulates, dimerizes ... HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1α in normoxia. EMBO J.22:4082-4090. ... 1A, compare lanes 7 and 3). Moreover, HIF1α was further induced by the hydroxylase inhibitor DMOG in Phd2−/− MEFs but not in ... A Feedback Loop Involving the Phd3 Prolyl Hydroxylase Tunes the Mammalian Hypoxic Response In Vivo. Yoji Andrew Minamishima, ...
The aryl hydrocarbon hydroxylase activity was not related to the mucosal histology, but the epoxide hydrolase and glutathione ...
Aryl hydrocarbon hydroxylase inducibility and bronochogenic carcinoma. New Engl J Med 289:934-937.. Khera, KS. 1991. Chemically ... Some sequences are clearly orthologous across many species-for example, only one CYP17 (steroid 17α-hydroxylase) gene has been ... due to induction by polycyclic hydrocarbons present in the smoke. The levels of CYP1A1 and CYP1A2 activity are therefore ...
Aryl hydrocarbon (benzo[a]pyrene) hydroxylase in guinea pig lymphoid tissue.. Bast RC Jr, Miller H, Rapp HJ, Gelboin HV.. J ... Interindividual and intraindividual variations in aryl hydrocarbon hydroxylase in monocytes from monozygotic and dizygotic ...
This is the mechanism of inhibition of aryl hydrocarbon hydroxylase by menadione in reconstituted systems. The causal roles of ...
Aryl Hydrocarbon Hydroxylases/chemistry/genetics *Cytochrome P-450 CYP1A1/chemistry/genetics *DNA/chemistry/genetics ...
Evidence that the binding species is receptor for induction of aryl hydrocarbon hydroxylase.; J Biol Chem, 1976 PubMed Europe ... Role of the aryl hydrocarbon receptor nuclear translocator protein in aryl hydrocarbon (dioxin) receptor action.; Mol ... Aryl Hydrocarbon Receptor Netpath (Homo sapiens). From WikiPathways. Revision as of 10:48, 23 December 2013 by Prakamya1986 ( ... Kim DW, Gazourian L, Quadri SA, Romieu-Mourez R, Sherr DH, Sonenshein GE; The RelA NF-kappaB subunit and the aryl hydrocarbon ...
Aryl Hydrocarbon Hydroxylases / genetics* Actions. * Search in PubMed * Search in MeSH * Add to Search ...
  • 1994 demonstrated that the administration of inhibitors of kynurenine hydroxylase and kynureninase, evoked a significant increase in brain levels of KYNA which protected the rats from electroshock induced seizures or DBA/2 mice from audiogenic seizures (Carpenedo et al. (ukessays.com)
  • Three examples of pharmacogenetic risk factors are discussed: the first two are p450 enzymes whose activity has been associated with susceptibility to lung cancer (debrisoquine hydroxylase, aryl hydrocarbon hydroxylase), and the last, N-acetyltransferase, a non-p450 enzyme, has been associated with bladder cancer susceptibility. (termsreign.tk)
  • Zebrafish CYP1A expression in transgenic Caenorhabditis elegans protects from exposures to benzo[a]pyrene and a complex polycyclic aromatic hydrocarbon mixture. (duke.edu)
  • Polycyclic Aromatic Hydrocarbon and Hypoxia Exposures Result in Mitochondrial Dysfunction in Zebrafish. (duke.edu)
  • Before the identification of CYP1B1 as a novel metabolic enzyme, it has been detected in mouse endometrial stromal cells as a polycyclic aromatic hydrocarbon-inducible CYP ( 2 ) and was subsequently characterized ( 3 ). (aacrjournals.org)
  • Alternative pathways of xanthone biosynthesis in cell cultures of Hypericum androsaemum L. Werner Schmidt and Ludger Beerhues, FEBS Letters, Volume 420, Issues 2-3, 29 December 1997, Pages 143-146, doi:10.1016/S0014-5793(97)01507-X Matthias Boll , Georg Fuchs , Johann Heider "Anaerobic oxidation of aromatic compounds and hydrocarbons" Current Opinion in Chemical Biology 2002 Volume 6, pp. 604-611. (wikipedia.org)
  • The aryl hydrocarbon hydroxylase activity was not related to the mucosal histology, but the epoxide hydrolase and glutathione peroxidase activities were diminished in samples with severe villous atrophy as compared with normal mucosa. (termsreign.tk)
  • Rates of APND and testosterone 6β- and 16β-hydroxylase were little changed by BNF, indicating that these are not CYP1A activities in these fish. (elsevier.com)
  • This enzyme is responsible in part for the reductive dearomatization of aryl compounds mediated by bacteria under anaerobic conditions. (wikipedia.org)