Microsomes, Liver: Closed vesicles of fragmented endoplasmic reticulum created when liver cells or tissue are disrupted by homogenization. They may be smooth or rough.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)Cytochrome P-450 CYP3A: A cytochrome P-450 suptype that has specificity for a broad variety of lipophilic compounds, including STEROIDS; FATTY ACIDS; and XENOBIOTICS. This enzyme has clinical significance due to its ability to metabolize a diverse array of clinically important drugs such as CYCLOSPORINE; VERAPAMIL; and MIDAZOLAM. This enzyme also catalyzes the N-demethylation of ERYTHROMYCIN.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.Liver: A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances.Liver Diseases: Pathological processes of the LIVER.Cytochrome P-450 CYP2D6: A cytochrome P450 enzyme that catalyzes the hydroxylation of many drugs and environmental chemicals, such as DEBRISOQUINE; ADRENERGIC RECEPTOR ANTAGONISTS; and TRICYCLIC ANTIDEPRESSANTS. This enzyme is deficient in up to 10 percent of the Caucasian population.Cytochrome P-450 CYP1A2: A cytochrome P450 enzyme subtype that has specificity for relatively planar heteroaromatic small molecules, such as CAFFEINE and ACETAMINOPHEN.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.Liver Transplantation: The transference of a part of or an entire liver from one human or animal to another.Liver Neoplasms: Tumors or cancer of the LIVER.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.Liver Cirrhosis: Liver disease in which the normal microcirculation, the gross vascular anatomy, and the hepatic architecture have been variably destroyed and altered with fibrous septa surrounding regenerated or regenerating parenchymal nodules.Hydroxylation: Placing of a hydroxyl group on a compound in a position where one did not exist before. (Stedman, 26th ed)Liver Regeneration: Repair or renewal of hepatic tissue.Fatty Liver: Lipid infiltration of the hepatic parenchymal cells resulting in a yellow-colored liver. The abnormal lipid accumulation is usually in the form of TRIGLYCERIDES, either as a single large droplet or multiple small droplets. Fatty liver is caused by an imbalance in the metabolism of FATTY ACIDS.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.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.Mitochondria, Liver: Mitochondria in hepatocytes. As in all mitochondria, there are an outer membrane and an inner membrane, together creating two separate mitochondrial compartments: the internal matrix space and a much narrower intermembrane space. In the liver mitochondrion, an estimated 67% of the total mitochondrial proteins is located in the matrix. (From Alberts et al., Molecular Biology of the Cell, 2d ed, p343-4)Cytochrome P-450 CYP2B1: A major cytochrome P-450 enzyme which is inducible by PHENOBARBITAL in both the LIVER and SMALL INTESTINE. It is active in the metabolism of compounds like pentoxyresorufin, TESTOSTERONE, and ANDROSTENEDIONE. This enzyme, encoded by CYP2B1 gene, also mediates the activation of CYCLOPHOSPHAMIDE and IFOSFAMIDE to MUTAGENS.Dealkylation: The removing of alkyl groups from a compound. (From McGraw-Hill Dictionary of Scientific and Technical Terms, 5th ed)Liver Function Tests: Blood tests that are used to evaluate how well a patient's liver is working and also to help diagnose liver conditions.Drug-Induced Liver Injury: A spectrum of clinical liver diseases ranging from mild biochemical abnormalities to ACUTE LIVER FAILURE, caused by drugs, drug metabolites, and chemicals from the environment.Steroid Hydroxylases: Cytochrome P-450 monooxygenases (MIXED FUNCTION OXYGENASES) that are important in steroid biosynthesis and metabolism.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 22.214.171.124.Kinetics: The rate dynamics in chemical or physical systems.Hepatocytes: The main structural component of the LIVER. They are specialized EPITHELIAL CELLS that are organized into interconnected plates called lobules.Glucuronides: Glycosides of GLUCURONIC ACID formed by the reaction of URIDINE DIPHOSPHATE GLUCURONIC ACID with certain endogenous and exogenous substances. Their formation is important for the detoxification of drugs, steroid excretion and BILIRUBIN metabolism to a more water-soluble compound that can be eliminated in the URINE and BILE.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.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.Liver Neoplasms, Experimental: Experimentally induced tumors of the LIVER.NADPH-Ferrihemoprotein Reductase: A flavoprotein that catalyzes the reduction of heme-thiolate-dependent monooxygenases and is part of the microsomal hydroxylating system. EC 126.96.36.199.Ketoconazole: Broad spectrum antifungal agent used for long periods at high doses, especially in immunosuppressed patients.Chromatography, High Pressure Liquid: Liquid chromatographic techniques which feature high inlet pressures, high sensitivity, and high speed.Isoenzymes: Structurally related forms of an enzyme. Each isoenzyme has the same mechanism and classification, but differs in its chemical, physical, or immunological characteristics.Rats, Inbred Strains: Genetically identical individuals developed from brother and sister matings which have been carried out for twenty or more generations or by parent x offspring matings carried out with certain restrictions. This also includes animals with a long history of closed colony breeding.Liver Extracts: Extracts of liver tissue containing uncharacterized specific factors with specific activities; a soluble thermostable fraction of mammalian liver is used in the treatment of pernicious anemia.Liver Circulation: The circulation of BLOOD through the LIVER.Troleandomycin: A macrolide antibiotic that is similar to ERYTHROMYCIN.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.Oxidoreductases, N-DemethylatingLiver Failure, Acute: A form of rapid-onset LIVER FAILURE, also known as fulminant hepatic failure, caused by severe liver injury or massive loss of HEPATOCYTES. It is characterized by sudden development of liver dysfunction and JAUNDICE. Acute liver failure may progress to exhibit cerebral dysfunction even HEPATIC COMA depending on the etiology that includes hepatic ISCHEMIA, drug toxicity, malignant infiltration, and viral hepatitis such as post-transfusion HEPATITIS B and HEPATITIS C.Liver Diseases, Alcoholic: Liver diseases associated with ALCOHOLISM. It usually refers to the coexistence of two or more subentities, i.e., ALCOHOLIC FATTY LIVER; ALCOHOLIC HEPATITIS; and ALCOHOLIC CIRRHOSIS.Liver Abscess: Solitary or multiple collections of PUS within the liver as a result of infection by bacteria, protozoa, or other agents.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.NADP: Nicotinamide adenine dinucleotide phosphate. A coenzyme composed of ribosylnicotinamide 5'-phosphate (NMN) coupled by pyrophosphate linkage to the 5'-phosphate adenosine 2',5'-bisphosphate. It serves as an electron carrier in a number of reactions, being alternately oxidized (NADP+) and reduced (NADPH). (Dorland, 27th ed)Methylcholanthrene: A carcinogen that is often used in experimental cancer studies.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).Rats, Sprague-Dawley: A strain of albino rat used widely for experimental purposes because of its calmness and ease of handling. It was developed by the Sprague-Dawley Animal Company.Hepatectomy: Excision of all or part of the liver. (Dorland, 28th ed)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.Proadifen: An inhibitor of drug metabolism and CYTOCHROME P-450 ENZYME SYSTEM activity.Substrate Specificity: A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts.Uridine Diphosphate Glucuronic Acid: A nucleoside diphosphate sugar which serves as a source of glucuronic acid for polysaccharide biosynthesis. It may also be epimerized to UDP iduronic acid, which donates iduronic acid to polysaccharides. In animals, UDP glucuronic acid is used for formation of many glucosiduronides with various aglycones.Chlorzoxazone: A centrally acting central muscle relaxant with sedative properties. It is claimed to inhibit muscle spasm by exerting an effect primarily at the level of the spinal cord and subcortical areas of the brain. (From Martindale, The Extra Pharmacopoea, 30th ed, p1202)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.Sulfaphenazole: A sulfonilamide anti-infective agent.Coumarins: Synthetic or naturally occurring substances related to coumarin, the delta-lactone of coumarinic acid.Liver Cirrhosis, Experimental: Experimentally induced chronic injuries to the parenchymal cells in the liver to achieve a model for LIVER CIRRHOSIS.beta-Naphthoflavone: A polyaromatic hydrocarbon inducer of P4501A1 and P4501A2 cytochromes. (Proc Soc Exp Biol Med 1994 Dec:207(3):302-308)Rats, Wistar: A strain of albino rat developed at the Wistar Institute that has spread widely at other institutions. This has markedly diluted the original strain.Cytochrome P-450 CYP2E1: An ethanol-inducible cytochrome P450 enzyme that metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Substrates include ETHANOL; INHALATION ANESTHETICS; BENZENE; ACETAMINOPHEN and other low molecular weight compounds. CYP2E1 has been used as an enzyme marker in the study of alcohol abuse.Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug.Liver Cirrhosis, Alcoholic: FIBROSIS of the hepatic parenchyma due to chronic excess ALCOHOL DRINKING.Stereoisomerism: The phenomenon whereby compounds whose molecules have the same number and kind of atoms and the same atomic arrangement, but differ in their spatial relationships. (From McGraw-Hill Dictionary of Scientific and Technical Terms, 5th ed)Phenacetin: A phenylacetamide that was formerly used in ANALGESICS but nephropathy and METHEMOGLOBINEMIA led to its withdrawal from the market. (From Smith and Reynard, Textbook of Pharmacology,1991, p431)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.Midazolam: A short-acting hypnotic-sedative drug with anxiolytic and amnestic properties. It is used in dentistry, cardiac surgery, endoscopic procedures, as preanesthetic medication, and as an adjunct to local anesthesia. The short duration and cardiorespiratory stability makes it useful in poor-risk, elderly, and cardiac patients. It is water-soluble at pH less than 4 and lipid-soluble at physiological pH.Cytochromes b5: Cytochromes of the b group that are found bound to cytoplasmic side of ENDOPLASMIC RETICULUM. They serve as electron carrier proteins for a variety of membrane-bound OXYGENASES. They are reduced by the enzyme CYTOCHROME-B(5) REDUCTASE.Alanine Transaminase: An enzyme that catalyzes the conversion of L-alanine and 2-oxoglutarate to pyruvate and L-glutamate. (From Enzyme Nomenclature, 1992) EC 188.8.131.52.Metabolic Detoxication, Phase I: Functionalization of exogenous substances to prepare them for conjugation in PHASE II DETOXIFICATION. Phase I enzymes include CYTOCHROME P450 enzymes and some OXIDOREDUCTASES. Excess induction of phase I over phase II detoxification leads to higher levels of FREE RADICALS that can induce CANCER and other cell damage. Induction or antagonism of phase I detoxication is the basis of a number of DRUG INTERACTIONS.Liver, Artificial: Devices for simulating the activities of the liver. They often consist of a hybrid between both biological and artificial materials.Liver Glycogen: Glycogen stored in the liver. (Dorland, 28th ed)Carcinoma, Hepatocellular: A primary malignant neoplasm of epithelial liver cells. It ranges from a well-differentiated tumor with EPITHELIAL CELLS indistinguishable from normal HEPATOCYTES to a poorly differentiated neoplasm. The cells may be uniform or markedly pleomorphic, or form GIANT CELLS. Several classification schemes have been suggested.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.Recombinant Proteins: Proteins prepared by recombinant DNA technology.Cytochrome ReductasesAlkane 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.Oxygenases: Oxidases that specifically introduce DIOXYGEN-derived oxygen atoms into a variety of organic molecules.Rabbits: The species Oryctolagus cuniculus, in the family Leporidae, order LAGOMORPHA. Rabbits are born in burrows, furless, and with eyes and ears closed. In contrast with HARES, rabbits have 22 chromosome pairs.Dextromethorphan: Methyl analog of DEXTRORPHAN that shows high affinity binding to several regions of the brain, including the medullary cough center. This compound is an NMDA receptor antagonist (RECEPTORS, N-METHYL-D-ASPARTATE) and acts as a non-competitive channel blocker. It is one of the widely used ANTITUSSIVES, and is also used to study the involvement of glutamate receptors in neurotoxicity.End Stage Liver Disease: Final stage of a liver disease when the liver failure is irreversible and LIVER TRANSPLANTATION is needed.Time Factors: Elements of limited time intervals, contributing to particular results or situations.Quinidine: An optical isomer of quinine, extracted from the bark of the CHINCHONA tree and similar plant species. This alkaloid dampens the excitability of cardiac and skeletal muscles by blocking sodium and potassium currents across cellular membranes. It prolongs cellular ACTION POTENTIALS, and decreases automaticity. Quinidine also blocks muscarinic and alpha-adrenergic neurotransmission.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.Glucose-6-Phosphatase: An enzyme that catalyzes the conversion of D-glucose 6-phosphate and water to D-glucose and orthophosphate. EC 184.108.40.206.Kidney: Body organ that filters blood for the secretion of URINE and that regulates ion concentrations.Rats, Inbred F344Gene Expression Regulation, Enzymologic: Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control of gene action in enzyme synthesis.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.Base Sequence: The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence.Glucuronates: Derivatives of GLUCURONIC ACID. Included under this heading are a broad variety of acid forms, salts, esters, and amides that include the 6-carboxy glucose structure.Dose-Response Relationship, Drug: The relationship between the dose of an administered drug and the response of the organism to the drug.Subcellular Fractions: Components of a cell produced by various separation techniques which, though they disrupt the delicate anatomy of a cell, preserve the structure and physiology of its functioning constituents for biochemical and ultrastructural analysis. (From Alberts et al., Molecular Biology of the Cell, 2d ed, p163)Carbon Tetrachloride: A solvent for oils, fats, lacquers, varnishes, rubber waxes, and resins, and a starting material in the manufacturing of organic compounds. Poisoning by inhalation, ingestion or skin absorption is possible and may be fatal. (Merck Index, 11th ed)Nitrosamines: A class of compounds that contain a -NH2 and a -NO radical. Many members of this group have carcinogenic and mutagenic properties.Intracellular Membranes: Thin structures that encapsulate subcellular structures or ORGANELLES in EUKARYOTIC CELLS. They include a variety of membranes associated with the CELL NUCLEUS; the MITOCHONDRIA; the GOLGI APPARATUS; the ENDOPLASMIC RETICULUM; LYSOSOMES; PLASTIDS; and VACUOLES.Tissue Distribution: Accumulation of a drug or chemical substance in various organs (including those not relevant to its pharmacologic or therapeutic action). This distribution depends on the blood flow or perfusion rate of the organ, the ability of the drug to penetrate organ membranes, tissue specificity, protein binding. The distribution is usually expressed as tissue to plasma ratios.Dogs: The domestic dog, Canis familiaris, comprising about 400 breeds, of the carnivore family CANIDAE. They are worldwide in distribution and live in association with people. (Walker's Mammals of the World, 5th ed, p1065)Mass Spectrometry: An analytical method used in determining the identity of a chemical based on its mass using mass analyzers/mass spectrometers.Endoplasmic Reticulum: A system of cisternae in the CYTOPLASM of many cells. In places the endoplasmic reticulum is continuous with the plasma membrane (CELL MEMBRANE) or outer membrane of the nuclear envelope. If the outer surfaces of the endoplasmic reticulum membranes are coated with ribosomes, the endoplasmic reticulum is said to be rough-surfaced (ENDOPLASMIC RETICULUM, ROUGH); otherwise it is said to be smooth-surfaced (ENDOPLASMIC RETICULUM, SMOOTH). (King & Stansfield, A Dictionary of Genetics, 4th ed)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.Benzopyrene 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 220.127.116.11.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)Glutathione: A tripeptide with many roles in cells. It conjugates to drugs to make them more soluble for excretion, is a cofactor for some enzymes, is involved in protein disulfide bond rearrangement and reduces peroxides.Hepatitis: INFLAMMATION of the LIVER.Catalysis: The facilitation of a chemical reaction by material (catalyst) that is not consumed by the reaction.Ethanol: A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in ALCOHOLIC BEVERAGES.Xenobiotics: Chemical substances that are foreign to the biological system. They include naturally occurring compounds, drugs, environmental agents, carcinogens, insecticides, etc.Intestines: The section of the alimentary canal from the STOMACH to the ANAL CANAL. It includes the LARGE INTESTINE and SMALL INTESTINE.Benzopyrenes: A class of chemicals that contain an anthracene ring with a naphthalene ring attached to it.Bilirubin: A bile pigment that is a degradation product of HEME.Acyltransferases: Enzymes from the transferase class that catalyze the transfer of acyl groups from donor to acceptor, forming either esters or amides. (From Enzyme Nomenclature 1992) EC 2.3.Polymorphism, Genetic: The regular and simultaneous occurrence in a single interbreeding population of two or more discontinuous genotypes. The concept includes differences in genotypes ranging in size from a single nucleotide site (POLYMORPHISM, SINGLE NUCLEOTIDE) to large nucleotide sequences visible at a chromosomal level.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.Organ Specificity: Characteristic restricted to a particular organ of the body, such as a cell type, metabolic response or expression of a particular protein or antigen.Cholesterol 7-alpha-Hydroxylase: A membrane-bound cytochrome P450 enzyme that catalyzes the 7-alpha-hydroxylation of CHOLESTEROL in the presence of molecular oxygen and NADPH-FERRIHEMOPROTEIN REDUCTASE. This enzyme, encoded by CYP7, converts cholesterol to 7-alpha-hydroxycholesterol which is the first and rate-limiting step in the synthesis of BILE ACIDS.Epoxide Hydrolases: Enzymes that catalyze reversibly the formation of an epoxide or arene oxide from a glycol or aromatic diol, respectively.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.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.Dimethylnitrosamine: A nitrosamine derivative with alkylating, carcinogenic, and mutagenic properties. It causes serious liver damage and is a hepatocarcinogen in rodents.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.Tetrachlorodibenzodioxin: 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.Bile: An emulsifying agent produced in the LIVER and secreted into the DUODENUM. Its composition includes BILE ACIDS AND SALTS; CHOLESTEROL; and ELECTROLYTES. It aids DIGESTION of fats in the duodenum.Steroid 17-alpha-Hydroxylase: A microsomal cytochrome P450 enzyme that catalyzes the 17-alpha-hydroxylation of progesterone or pregnenolone and subsequent cleavage of the residual two carbons at C17 in the presence of molecular oxygen and NADPH-FERRIHEMOPROTEIN REDUCTASE. This enzyme, encoded by CYP17 gene, generates precursors for glucocorticoid, androgen, and estrogen synthesis. Defects in CYP17 gene cause congenital adrenal hyperplasia (ADRENAL HYPERPLASIA, CONGENITAL) and abnormal sexual differentiation.Safrole: A member of the BENZODIOXOLES that is a constituent of several VOLATILE OILS, notably SASSAFRAS oil. It is a precursor in the synthesis of the insecticide PIPERONYL BUTOXIDE and the drug N-methyl-3,4-methylenedioxyamphetamine (MDMA).Dolichol: Eicosamethyl octacontanonadecasen-1-o1. Polyprenol found in animal tissues that contains about 20 isoprene residues, the one carrying the alcohol group being saturated.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).Metabolic Clearance Rate: Volume of biological fluid completely cleared of drug metabolites as measured in unit time. Elimination occurs as a result of metabolic processes in the kidney, liver, saliva, sweat, intestine, heart, brain, or other site.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.Fatty Acids: Organic, monobasic acids derived from hydrocarbons by the equivalent of oxidation of a methyl group to an alcohol, aldehyde, and then acid. Fatty acids are saturated and unsaturated (FATTY ACIDS, UNSATURATED). (Grant & Hackh's Chemical Dictionary, 5th ed)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.Kupffer Cells: Specialized phagocytic cells of the MONONUCLEAR PHAGOCYTE SYSTEM found on the luminal surface of the hepatic sinusoids. They filter bacteria and small foreign proteins out of the blood, and dispose of worn out red blood cells.Oxidoreductases, O-Demethylating: Drug metabolizing enzymes which oxidize methyl ethers. Usually found in liver microsomes.Gas Chromatography-Mass Spectrometry: A microanalytical technique combining mass spectrometry and gas chromatography for the qualitative as well as quantitative determinations of compounds.Aflatoxin B1: A potent hepatotoxic and hepatocarcinogenic mycotoxin produced by the Aspergillus flavus group of fungi. It is also mutagenic, teratogenic, and causes immunosuppression in animals. It is found as a contaminant in peanuts, cottonseed meal, corn, and other grains. The mycotoxin requires epoxidation to aflatoxin B1 2,3-oxide for activation. Microsomal monooxygenases biotransform the toxin to the less toxic metabolites aflatoxin M1 and Q1.Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides see GLYCEROPHOSPHOLIPIDS) or sphingosine (SPHINGOLIPIDS). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system.Hydroxytestosterones: 17 beta-Hydroxy-4-androsten-3-ones. Testosterone derivatives formed by the substitution of one or more hydroxyl groups in any position.Organ Size: The measurement of an organ in volume, mass, or heaviness.Membranes: Thin layers of tissue which cover parts of the body, separate adjacent cavities, or connect adjacent structures.Receptors, Cytoplasmic and Nuclear: Intracellular receptors that can be found in the cytoplasm or in the nucleus. They bind to extracellular signaling molecules that migrate through or are transported across the CELL MEMBRANE. Many members of this class of receptors occur in the cytoplasm and are transported to the CELL NUCLEUS upon ligand-binding where they signal via DNA-binding and transcription regulation. Also included in this category are receptors found on INTRACELLULAR MEMBRANES that act via mechanisms similar to CELL SURFACE RECEPTORS.Lipid Metabolism: Physiological processes in biosynthesis (anabolism) and degradation (catabolism) of LIPIDS.Acetaminophen: Analgesic antipyretic derivative of acetanilide. It has weak anti-inflammatory properties and is used as a common analgesic, but may cause liver, blood cell, and kidney damage.Steroid 21-Hydroxylase: An adrenal microsomal cytochrome P450 enzyme that catalyzes the 21-hydroxylation of steroids in the presence of molecular oxygen and NADPH-FERRIHEMOPROTEIN REDUCTASE. This enzyme, encoded by CYP21 gene, converts progesterones to precursors of adrenal steroid hormones (CORTICOSTERONE; HYDROCORTISONE). Defects in CYP21 cause congenital adrenal hyperplasia (ADRENAL HYPERPLASIA, CONGENITAL).Chromatography, Liquid: Chromatographic techniques in which the mobile phase is a liquid.Benzphetamine: A sympathomimetic agent with properties similar to DEXTROAMPHETAMINE. It is used in the treatment of obesity. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1222)Orphenadrine: A muscarinic antagonist used to treat drug-induced parkinsonism and to relieve pain from muscle spasm.Spectrophotometry, Ultraviolet: Determination of the spectra of ultraviolet absorption by specific molecules in gases or liquids, for example Cl2, SO2, NO2, CS2, ozone, mercury vapor, and various unsaturated compounds. (McGraw-Hill Dictionary of Scientific and Technical Terms, 4th ed)Pharmaceutical Preparations: Drugs intended for human or veterinary use, presented in their finished dosage form. Included here are materials used in the preparation and/or formulation of the finished dosage form.Clofibrate: A fibric acid derivative used in the treatment of HYPERLIPOPROTEINEMIA TYPE III and severe HYPERTRIGLYCERIDEMIA. (From Martindale, The Extra Pharmacopoeia, 30th ed, p986)Genotype: The genetic constitution of the individual, comprising the ALLELES present at each GENETIC LOCUS.Swine: Any of various animals that constitute the family Suidae and comprise stout-bodied, short-legged omnivorous mammals with thick skin, usually covered with coarse bristles, a rather long mobile snout, and small tail. Included are the genera Babyrousa, Phacochoerus (wart hogs), and Sus, the latter containing the domestic pig (see SUS SCROFA).Carboxylic Ester Hydrolases: Enzymes which catalyze the hydrolysis of carboxylic acid esters with the formation of an alcohol and a carboxylic acid anion.Neoplasms, Germ Cell and Embryonal: Neoplasms composed of primordial GERM CELLS of embryonic GONADS or of elements of the germ layers of the EMBRYO, MAMMALIAN. The concept does not refer to neoplasms located in the gonads or present in an embryo or FETUS.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.Bile Acids and Salts: Steroid acids and salts. The primary bile acids are derived from cholesterol in the liver and usually conjugated with glycine or taurine. The secondary bile acids are further modified by bacteria in the intestine. They play an important role in the digestion and absorption of fat. They have also been used pharmacologically, especially in the treatment of gallstones.Gene Expression: The phenotypic manifestation of a gene or genes by the processes of GENETIC TRANSCRIPTION and GENETIC TRANSLATION.Cell Line: Established cell cultures that have the potential to propagate indefinitely.Cell Fractionation: Techniques to partition various components of the cell into SUBCELLULAR FRACTIONS.Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils.Portal Vein: A short thick vein formed by union of the superior mesenteric vein and the splenic vein.Epoxy Compounds: Organic compounds that include a cyclic ether with three ring atoms in their structure. They are commonly used as precursors for POLYMERS such as EPOXY RESINS.Perfusion: Treatment process involving the injection of fluid into an organ or tissue.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.Carbon Tetrachloride PoisoningMephenytoin: An anticonvulsant effective in tonic-clonic epilepsy (EPILEPSY, TONIC-CLONIC). It may cause blood dyscrasias.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.Polyisoprenyl Phosphate Monosaccharides: These compounds function as activated monosaccharide carriers in the biosynthesis of glycoproteins and oligosaccharide phospholipids. Obtained from a nucleoside diphosphate sugar and a polyisoprenyl phosphate.Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes.Cattle: Domesticated bovine animals of the genus Bos, usually kept on a farm or ranch and used for the production of meat or dairy products or for heavy labor.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.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.Debrisoquin: An adrenergic neuron-blocking drug similar in effects to GUANETHIDINE. It is also noteworthy in being a substrate for a polymorphic cytochrome P-450 enzyme. Persons with certain isoforms of this enzyme are unable to properly metabolize this and many other clinically important drugs. They are commonly referred to as having a debrisoquin 4-hydroxylase polymorphism.Diethylnitrosamine: A nitrosamine derivative with alkylating, carcinogenic, and mutagenic properties.Biological Transport: The movement of materials (including biochemical substances and drugs) through a biological system at the cellular level. The transport can be across cell membranes and epithelial layers. It also can occur within intracellular compartments and extracellular compartments.Cytochromes: Hemeproteins whose characteristic mode of action involves transfer of reducing equivalents which are associated with a reversible change in oxidation state of the prosthetic group. Formally, this redox change involves a single-electron, reversible equilibrium between the Fe(II) and Fe(III) states of the central iron atom (From Enzyme Nomenclature, 1992, p539). The various cytochrome subclasses are organized by the type of HEME and by the wavelength range of their reduced alpha-absorption bands.Fluvoxamine: A selective serotonin reuptake inhibitor that is used in the treatment of DEPRESSION and a variety of ANXIETY DISORDERS.Lipid Peroxides: Peroxides produced in the presence of a free radical by the oxidation of unsaturated fatty acids in the cell in the presence of molecular oxygen. The formation of lipid peroxides results in the destruction of the original lipid leading to the loss of integrity of the membranes. They therefore cause a variety of toxic effects in vivo and their formation is considered a pathological process in biological systems. Their formation can be inhibited by antioxidants, such as vitamin E, structural separation or low oxygen tension.Testosterone: A potent androgenic steroid and major product secreted by the LEYDIG CELLS of the TESTIS. Its production is stimulated by LUTEINIZING HORMONE from the PITUITARY GLAND. In turn, testosterone exerts feedback control of the pituitary LH and FSH secretion. Depending on the tissues, testosterone can be further converted to DIHYDROTESTOSTERONE or ESTRADIOL.2-Acetylaminofluorene: A hepatic carcinogen whose mechanism of activation involves N-hydroxylation to the aryl hydroxamic acid followed by enzymatic sulfonation to sulfoxyfluorenylacetamide. It is used to study the carcinogenicity and mutagenicity of aromatic amines.Immunochemistry: Field of chemistry that pertains to immunological phenomena and the study of chemical reactions related to antigen stimulation of tissues. It includes physicochemical interactions between antigens and antibodies.Palmitoyl Coenzyme A: A fatty acid coenzyme derivative which plays a key role in fatty acid oxidation and biosynthesis.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.Acyl Coenzyme A: S-Acyl coenzyme A. Fatty acid coenzyme A derivatives that are involved in the biosynthesis and oxidation of fatty acids as well as in ceramide formation.Hydrogen-Ion Concentration: The normality of a solution with respect to HYDROGEN ions; H+. It is related to acidity measurements in most cases by pH = log 1/2[1/(H+)], where (H+) is the hydrogen ion concentration in gram equivalents per liter of solution. (McGraw-Hill Dictionary of Scientific and Technical Terms, 6th ed)Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors.Bile Ducts: The channels that collect and transport the bile secretion from the BILE CANALICULI, the smallest branch of the BILIARY TRACT in the LIVER, through the bile ductules, the bile ducts out the liver, and to the GALLBLADDER for storage.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.Hepatic Artery: A branch of the celiac artery that distributes to the stomach, pancreas, duodenum, liver, gallbladder, and greater omentum.Mutagenicity Tests: Tests of chemical substances and physical agents for mutagenic potential. They include microbial, insect, mammalian cell, and whole animal tests.Aminopyrine N-DemethylaseReceptors, Steroid: Proteins found usually in the cytoplasm or nucleus that specifically bind steroid hormones and trigger changes influencing the behavior of cells. The steroid receptor-steroid hormone complex regulates the transcription of specific genes.Hep G2 Cells: A human liver tumor cell line used to study a variety of liver-specific metabolic functions.Lung: Either of the pair of organs occupying the cavity of the thorax that effect the aeration of the blood.Metyrapone: An inhibitor of the enzyme STEROID 11-BETA-MONOOXYGENASE. It is used as a test of the feedback hypothalamic-pituitary mechanism in the diagnosis of CUSHING SYNDROME.Cytochrome-B(5) Reductase: A FLAVOPROTEIN oxidoreductase that occurs both as a soluble enzyme and a membrane-bound enzyme due to ALTERNATIVE SPLICING of a single mRNA. The soluble form is present mainly in ERYTHROCYTES and is involved in the reduction of METHEMOGLOBIN. The membrane-bound form of the enzyme is found primarily in the ENDOPLASMIC RETICULUM and outer mitochondrial membrane, where it participates in the desaturation of FATTY ACIDS; CHOLESTEROL biosynthesis and drug metabolism. A deficiency in the enzyme can result in METHEMOGLOBINEMIA.NAD: A coenzyme composed of ribosylnicotinamide 5'-diphosphate coupled to adenosine 5'-phosphate by pyrophosphate linkage. It is found widely in nature and is involved in numerous enzymatic reactions in which it serves as an electron carrier by being alternately oxidized (NAD+) and reduced (NADH). (Dorland, 27th ed)Aromatase: An enzyme that catalyzes the desaturation (aromatization) of the ring A of C19 androgens and converts them to C18 estrogens. In this process, the 19-methyl is removed. This enzyme is membrane-bound, located in the endoplasmic reticulum of estrogen-producing cells of ovaries, placenta, testes, adipose, and brain tissues. Aromatase is encoded by the CYP19 gene, and functions in complex with NADPH-FERRIHEMOPROTEIN REDUCTASE in the cytochrome P-450 system.Acetone: A colorless liquid used as a solvent and an antiseptic. It is one of the ketone bodies produced during ketoacidosis.Living Donors: Non-cadaveric providers of organs for transplant to related or non-related recipients.Area Under Curve: A statistical means of summarizing information from a series of measurements on one individual. It is frequently used in clinical pharmacology where the AUC from serum levels can be interpreted as the total uptake of whatever has been administered. As a plot of the concentration of a drug against time, after a single dose of medicine, producing a standard shape curve, it is a means of comparing the bioavailability of the same drug made by different companies. (From Winslade, Dictionary of Clinical Research, 1992)
... in vitro experiments with rat and human liver microsomes suggest that the CYP450 enzyme CYP2E1 hydroxylates indole into indoxyl ... Subsequently, indoxyl is converted into indoxyl sulfate by sulfotransferase enzymes in the liver; based upon in vitro ... Indoxyl is produced from indole via enzyme-mediated hydroxylation in the liver; ...
Rawal S, Coulombe RA (August 2011). "Metabolism of aflatoxin B1 in turkey liver microsomes: the relative roles of cytochromes ... The CYP nomenclature is the official naming convention, although occasionally CYP450 or CYP450 is used synonymously. However, ... Zhang JW, Liu Y, Cheng J, Li W, Ma H, Liu HT, Sun J, Wang LM, He YQ, Wang Y, Wang ZT, Yang L (2007). "Inhibition of human liver ... reducing the Fe-O2 adduct to give a short-lived peroxo state. ... principally in the liver. The Human Genome Project has ...
In humans, a subset of Cytochrome P450 (CYP450) microsome-bound ω-hydroxylases (termed Cytochrome P450 omega hydroxylases) ... In vertebrates, the enzymes for ω oxidation are located in the smooth ER of liver and kidney cells, instead of in the ... Among the CYP450 superfamily, members of the CYP4A and CYP4F subfamilies viz., CYP4A11, CYP4F2, CYP4F3, are considered the ...
A subset of Cytochrome P450 (CYP450) microsome-bound ω-hydroxylases, the Cytochrome P450 omega hydroxylases, metabolize ... 20-HETE-synthesizng enzymes are widely distributed to liver, kidney, brain, lung, intestine and blood vessels. In most vascular ... CYP450 enzymes belong to a superfamily which in humans is composed of at least 57 members and in mice at least 120 members. ... CYP4F3B mostly in the liver. Human CYP4Z1, which is expressed in a limited range of tissues such as human breast and ovary, may ...
... makes up about 18% of the cytochrome P450 protein in liver microsomes (data only for antifungal). Some 100 therapeutic ... have actions which often oppose those of another product of CYP450 enzymes (e.g. CYP4A1, CYP4A11, CYP4F2, CYP4F3A, and CYP4F3B ... limonenes to respective carveols and perillyl alcohols by CYP2C9 and CYP2C19 in human liver microsomes". Drug Metabolism and ... "Role of cytochrome P-4502C9 in irbesartan oxidation by human liver microsomes". Drug Metabolism and Disposition. 27 (2): 288-96 ...
"Orphenadrine and methimazole inhibit multiple cytochrome P450 enzymes in human liver microsomes". Drug Metab. Dispos. 25 (3): ... Svärd J, Spiers JP, Mulcahy F, Hennessy M (2010). "Nuclear Receptor-Mediated Induction of CYP450 by Antiretrovirals: Functional ...
Buratti, F.M. (2003). "CYP-specific bioactivation of four organophosphorothioate pesticides by human liver microsomes". Toxicol ... Gutoxon can again be detoxified with the help of CYP450. CYP450 catalyzes the oxidative cleavage of gutoxon, which than yields ... With little bioactivity and no exposure to UV light, it can reach half-lives of roughly a year. Possible effects on animals are ... doi:10.1016/0041-008x(88)90259-1. Motoyama N, D.W. (1972). The in vitro metabolism of azinphosmethyl by mouse liver. Pesticide ...
Comparison of human liver and kidney microsomes and mammalian enzymes". Biochemical Pharmacology. 60 (1): 7-17. doi:10.1016/ ... Prior to the 1960s, the oxidation of xenotoxic materials was thought to be completely accomplished by CYP450. However, in the ... While the adult liver is dominated by the expression of FMO3 and FMO5, the fetal liver is dominated by the expression of FMO1 ... FMO3 is highly concentrated in the liver, but is also expressed in the lungs. FMO4 is expressed mostly in the liver and kidneys ...
The epidemic in 1998 at New Delhi, India is the largest so far, in which over 60 persons lost their lives and more than 3000 ... Eruvaram, N. R.; Das, M. (2009). "Phenotype of Hepatic Xenobiotic Metabolizing Enzymes and CYP450 Isoforms of Sanguinarine ... in AO induced toxicity causing peroxidative damage of lipids in various hepatic sub-cellular fractions including microsomes and ... Delayed clearance:Destruction of hepatic cytochrome P450 significantly affects the metabolic clearance by liver,. The retention ...
... and CYP2C19 are responsible for the in vitro N-demethylation of meperidine in human liver microsomes". Drug Metabolism and ... more potent than the CYP450 epoxygenase (e.g. CYP2C8, CYP2C9, CYP2C19, CYP2J2, and CYP2S1)-formed epoxides of arachidonic acid ... "Identification of CYP4A11 as the major lauric acid omega-hydroxylase in human liver microsomes". Archives of Biochemistry and ... CYP4A11 is highly expressed in the liver and kidney. CYP4A11 along with CYP4A22, CYP4F2, and CYP4F3 metabolize arachidonic acid ...
After acute exposure, severe liver damage is noticeable by a disruption of liver cell structure. The liver weight will increase ... to which CYP450 is converted. Together with the fact that mice with an induced higher concentration CYP450 are less affected by ... 1987 Distribution of Microcystis aeruginosa peptide toxin and interactions with hepatic microsomes in mice Pharmacol. Toxicol ... Liver damage could be noticed in 20 minutes. Within a few hours, liver cells died. Acute microcystin-LR intoxication may result ...
... in rat and human urine and human liver microsomes using GC-MS and LC-high-resolution MS and its detectability in urine by GC-MS ... All this suggests an increased vulnerability to cocaine abuse MDPV undergoes CYP450 2D6, 2C19, 1A2, and COMT phase 1 metabolism ... liver) into methylcatechol and pyrrolidine, which in turn are glucuronated (uridine 5'-diphospho-glucuronosyl-transferase) ...
Finally, the product epoxides are short-lived in cells, generally existing for only several seconds before being converted by a ... as defined using recombinient CYPs in an In vitro microsome assay. CYP2C9, and CYP2J2 appear to be the main produces of the ... "Prevalence of CYP450 gene variations in patients with type 2 diabetes". Clinical laboratory. 56 (7-8): 311-8. PMID 20857895. ... CYP2S1 is expressed in macrophages, liver, lung, intestine, and spleen and is abundant in human and mouse atherosclerosis (i.e ...
Rawal S, Coulombe RA (August 2011). "Metabolism of aflatoxin B1 in turkey liver microsomes: the relative roles of cytochromes ... The CYP nomenclature is the official naming convention, although occasionally CYP450 or CYP450 is used synonymously. However, ... principally in the liver. The Human Genome Project has identified 57 human genes coding for the various cytochrome P450 enzymes ... reducing the Fe-O2 adduct to give a short-lived peroxo state. The peroxo group formed in step 4 is rapidly protonated twice, ...
A subset of cytochrome P450 (CYP450) microsome-bound ω-hydroxylases (see 20-Hydroxyeicosatetraenoic acid) metabolize ... Longer lived TX analog Longer lived TX analog. Research only Cyclopentenone prostaglandins. Main article: Cyclopentenone ... Cytochrome P450 microsome ω-hydroxylases: CYP4A11, CYP4A22, CYP4F2, and CYP4F3 metabolize arachidonic acid primarily to 20- ...
MDPV undergoes CYP450 2D6, 2C19, 1A2, and COMT phase 1 metabolism (liver) into methylcatechol and pyrrolidine, which in ... in rat and human urine and human liver microsomes using GC-MS and LC-high-resolution MS and its detectability in urine by GC-MS ...
Further, quinine produced robust dose-dependent oxidative stress in human erythrocytes in the presence of microsomes. Taken in ... species generation was also measured in human erythrocytes incubated in the presence of quinine with and without microsomes. ... Zhao XJ, Ishizaki T: The In vitro hepatic metabolism of quinine in mice, rats and dogs: comparison with human liver microsomes ... Quinine was assayed in normal human erythrocytes in the presence and absence of pooled human liver microsomes. Quinine did not ...
... microsomes & other liver subcellular fractionsLarge pooled lots for reproducible, long-term studiesFractions carefully isolated ... Microsomes functionally tested for select CYP450 and Phase II enzyme activities. Request more information ... Table 1. Relevant applications for liver subcellular fractions.. Metabolic Enzymes. Liver Microsomes. Liver S9 Fractions. Liver ... Table 3. Kinetic parameters for the Gibco 50 donor human liver microsome pool.. Isoform. Metabolite. Km(μM). Vmax (nmol/min/mg) ...
In humans, sesamin is metabolized by CYP450 enzymes into sesamin mono- and di-catechol in liver microsomes (12). Sesamin ... 2010) Metabolism of sesamin by cytochrome P450 in human liver microsomes. Drug Metab Dispos 38(12):2117-2123. ... 2012) Metabolism of sesamin by CYPs and UGTs in human liver. J Food Drug Anal 20(1):376-379. ... 2003) Novel antioxidative metabolites in rat liver with ingested sesamin. J Agric Food Chem 51(6):1666-1670. ...
Rapidly Distinguishing Reversible and Time-Dependent CYP450 Inhibition Using Human Liver Microsomes, Co-incubation, and ... Identification of Time-Dependent CYP Inhibitors Using Human Liver Microsomes (HLM) Kevin J. Coe, Judith Skaptason, Tatiana ... Metabolic Assessment in Alamethicin-Activated Liver Microsomes: Co-activating CYPs and UGTs ...
microsomes indicate that MMAE inhibits CYP3A4/5 but not other CYP isoforms. MMAE did. not induce any major CYP450 enzymes in ... Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may also increase the risk. Monitor ... Advise patients to report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal ... that occurs is primarily via oxidation by CYP3A4/5. In vitro studies using human liver. ...
In vitro studies using human liver microsomes indicate that MMAE inhibits CYP3A4/5 but not other CYP isoforms. MMAE did not ... induce any major CYP450 enzymes in primary cultures of human hepatocytes.. Excretion ... Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may also increase the risk. Monitor ... Advise patients to report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal ...
In vitro metabolism studies with human liver microsomes demonstrated that bepotastine is minimally metabolized by CYP450 ... the concentration of radio-labeled bepotastine besilate was similar in fetal liver and maternal blood plasma. The concentration ...
... refers to the predicted half-life in human liver microsomes; T1/2 (M) refers to the predicted half-life in mouse liver ... F) JAG21 CYP450 Inhibition, CACO-2, hERG, PPB, BBB (MDCK-MDK1) efflux analyses. These were performed by Chem Partners and are ... Kinetic solubility and metabolic stability in human or murine liver microsomes were measured. The hERG (human Ether-à-go-go- ... E) Solubility and Stability in human and mouse liver microsomes comparing MJM 170, JAG21, and JAG50. Performed by Chem Partners ...
Purified liver endoplasmic reticulum. *Rough microsomes contain ribosomes. **Smooth microsomes contain mixed function oxidase ( ... Microsomal enzyme inhibition (many drugs inhibit CYP450). Microsomal enzyme induction. Plasma biding protein (drugs highly ... enzyme responsible for drug interactions in the liver.. **Drugs can inhibit or induce p450. If inhibited, then less drug is ... Heme-containing enzymes primarily found in liver hepatocytes and small intestine enterocytes. *Each enzyme is referred to as an ...
In human liver microsomes and recombinant CYP450 enzymes, the metabolism of artemether was catalyzed predominantly by CYP3A4/5 ... In human liver microsomes and in recombinant CYP450 enzymes, lumefantrine was metabolized mainly by CYP3A4 to desbutyl- ... The artemether: lumefantrine combination was evaluated using the Salmonella and Escherichia/mammalian-microsome mutagenicity ... post implantation loss and decreases in the number of live fetuses. No adverse reproductive effects were detected in rabbits at ...
Rawal S, Coulombe RA (August 2011). "Metabolism of aflatoxin B1 in turkey liver microsomes: the relative roles of cytochromes ... The CYP nomenclature is the official naming convention, although occasionally CYP450 or CYP450 is used synonymously. However, ... Zhang JW, Liu Y, Cheng J, Li W, Ma H, Liu HT, Sun J, Wang LM, He YQ, Wang Y, Wang ZT, Yang L (2007). "Inhibition of human liver ... reducing the Fe-O2 adduct to give a short-lived peroxo state. ... principally in the liver. The Human Genome Project has ...
In vitro inhibition studies in human liver microsomes suggest that cytochrome P450 (CYP) 1A2, 2C19 and 3A4 are involved in ... In vitro, teriflunomide is not metabolized by CYP450 or flavin monoamine oxidase enzymes. The parent compound is rarely ... Elevation of Liver Enzymes. Treatment with Leflunomide was associated with elevations of liver enzymes, primarily ALT and AST, ... Severe liver injury, including fatal liver failure, has been reported in some patients treated with Leflunomide. Patients with ...
... in vitro experiments with rat and human liver microsomes suggest that the CYP450 enzyme CYP2E1 hydroxylates indole into indoxyl ... Subsequently, indoxyl is converted into indoxyl sulfate by sulfotransferase enzymes in the liver; based upon in vitro ... Indoxyl is produced from indole via enzyme-mediated hydroxylation in the liver; ...
In vitro studies using human liver microsomes and recombinant CYP450 enzymes have shown that ivermectin is primarily ... The findings of in vitro studies using human liver microsomes suggest that clinically relevant concentrations of ivermectin do ... Ivermectin is metabolized in the liver, and ivermectin and/or its metabolites are excreted almost exclusively in the feces over ... and TA100 with and without rat liver enzyme activation, the Mouse Lymphoma Cell Line L5178Y (cytotoxicity and mutagenicity) ...
CYP450 enzymes are most abundant in the liver and induce metabolic activation of numerous xenobiotic compounds. The present ... Sprague Dawley rat liver microsomes (RLM), mouse liver microsomes (MLM), Dunkin Hartley guinea pig liver microsomes (PLM) and ... including human liver microsomes (HLM), Rhesus monkey liver microsomes (RMLM), Cynomolgus monkey liver microsomes (CMLM), ... and mouse liver microsomes, and human liver s9. Drug Metab Dispos. 40:2041-2053. 2012.PubMed/NCBI View Article : Google Scholar ...
Microsomes prepared from whole liver or isolated intestinal enterocytes demonstrated similar CYP450 and A-EST metabolic ... The affinity (Km) for the metabolism of CPF to CPF-oxon was the same in liver and enterocyte microsomes, however the Km for TCP ... CYP450 content, as measured by reduced CO spectra, was approximately 10-fold lower in enterocyte than hepatocyte microsomes. ... Due to the smaller volume of intestine, the lower amount of CYP450, and the higher Km for TCP in the enterocyte microsomes, the ...
In liver microsomes and recombinant CYP450 isozymes, SAM-760 was predominantly metabolized by CYP3A (~85%). Based on these ...
CYP2E1 is mainly present in liver microsomes and plays a critical role in ROS production and liver injury. Acute and chronic ... CYP2E1 is one of the main members of CYP450 family and the most relevant to ALD because of its high inducibility and high ... and the wet weight of the liver was weighed. The liver index was calculated by the following formula: liver index (%) = liver ... The liver was removed and weighed, and the liver index was calculated. The values are expressed as the means ± SEMs. vs. normal ...
In human liver microsomes, the mean IC50 for grapefruit juice versus CYP3A (triazolam alpha-hydroxylation) was 0.55%, without ... CYP 450 effects: Bergamottin, the primary furanocoumarin extracted from grapefruit juice, has been found to be a mechanism- ... and 3A4 in human liver microsomes.31 According to one randomized controlled study, bergamottin is likely responsible for drug ... did not inhibit the hydrolysis of PNPA by purified porcine esterase and human liver microsomes. However, the flavonoid ...
Liver microsomes. *Cryopreserved hepatocytes. *Other tissues and fluids. *CYP450 inhibition. *Plasma protein binding ...
... which is also metabolized by kidney microsomes. This is consistent with the fact that CYP450 2E1 is scarcely expressed in human ... Although the CYP450 2E1 concentration is highest in the liver, this cytochrome P450 isoenzyme has also been found in organs ... Studying the metabolism of sevoflurane and methoxyflurane by human kidney and liver microsomes, Kharash et al. 12 have shown ... 15 The lung microsomes are also three to four times less active than microsomes from the lung. 16 In two older children in whom ...
CYP450 effects: In an in vitro study of human liver microsomes, tangeretin found in tangerine juice potently and selectively ... CYP450 effects: In an in vitro study of human liver microsomes, tangeretin found in tangerine juice potently and ... or liver (Hep G2) cancer cells lines.8 In two in vitro studies, extracts of Citrus reticulata Blanco peel increased apoptosis ... indicating efficient cleavage in the intestine before the carotenoid is incorporated into lipoproteins by the liver. Other ...
Omura T., Sato R.J. (1964): The carbon-monoxide-binding pigment of liver microsomes. J. Biol. Chem., 239: 2370-2378.PubMed ... In this report, studies were undertaken to determine the effect ofPlasmodium berghei infection on cytochrome P-450 (CYP450) 2E1 ... Cytochrome P-450 liver microsomes Sprague-Dawley rats malaria Western blotting isozymes ... Effect of malaria infection and endotoxin-induced fever on phenacetin O-deethylation by rat liver microsomes. Biochem. ...
3.? In rat liver microsomes, gliquidone was metabolized mainly by the most abundant CYP2C. The other isoforms involved in the ... 2.? Cytochrome P450 (CYP450) isoforms are involved in the metabolism of a majority of drugs in clinical use and plays a ... 5.? But the metabolism of gliquidone in the human liver microsomes was mainly mediated by CYP3A4. The other isoforms involved ... play an essential role in helping B cells differentiation into long-lived plasma cells in germinal center (GC) or short-lived ...
At an early stage of drug development, rat liver microsomes (RLMs) with specific cytochrome P450 (CYP450) activity were ...
HepaticInhibitionSubstratesMetabolitesIsoformsHepatocytesMetabolism in human liver microsomesInhibitorsCYP3ARecombinant CYP450 enzymesInhibitMicrosomalStabilityCYP2E1Cytochrome P450 activityAssayIsozymesTissuesSuperfamilyP450Endoplasmic reticulumReactionsOxidative stressToxicityCYP2C19MiceRatsNADPHFlavonoidsIsoenzymesIntestinalCompoundsCYP2D6ProteinPlasmodiumSubcellularBiotransformationMammalianDonorsInduceStudiesEnzymes in the liverPigmentDetoxificationCYP2C9Rainbow troutPrimarilyInductionEnzyme systemSpecific
- The protein expression levels of hepatic cytochrome P450 2E1 (CYP2E1), nuclear factor erythroid 2-related factor 2 (Nrf2), antioxidant protein heme oxygenase-1 (HO-1), and nuclear factor-kappa B (NF- κ B) signaling pathway in liver tissues were detected by immunohistochemistry and Western blot methods. (hindawi.com)
- Taraxasterol significantly reduced the ethanol-induced increases of liver index, ALT, AST, and TG levels in sera and TG and MDA contents in the livers and hepatic ROS production and suppressed the ethanol-induced decreases of hepatic GSH level and SOD activity. (hindawi.com)
- Although the Km for the substrates were comparable in hepatic and enterocyte microsomes, the Vmax was significantly faster, 69- to 255-fold in liver. (cdc.gov)
- F ic measured in suspended human hepatocytes also reflected hepatic enrichment factors of CYP450 inhibitors used in physiologically-based pharmacokinetic modelling. (diva-portal.org)
- Also, as a protective mechanism for hepatic antioxidant defense systems, decreased liver MDA contents, increased glutathione contents, increased dismutase and catalase activities were observed when compared to the ethanol control. (e-sciencecentral.org)
- Hoveniae Semen Cum Fructus extract favorably protected against liver damages, mediated by its potent anti-inflammatory and anti-steatosis properties through the augmentation of the hepatic antioxidant defense system by NF-E2-related factor-2 activation, and down-regulation of the mRNA expression of hepatic lipogenic genes or up-regulation of the mRNA expression of genes involved in fatty acid oxidation. (e-sciencecentral.org)
- Hepatic microsomes can be obtained commercially, with or without prior phenotyping, for most important drug metabolizing enzymes. (pharmacistspharmajournal.org)
- Despite this hepatic tropism, the interaction of NPs with the detoxification function of the liver remains unclear. (biopredic.com)
- 11 The CYP3A4 isozyme accounts for over 25 percent of hepatic CYP450 content and is responsible for over half of all CYP450-mediated drug metabolisms. (podiatrytoday.com)
- This study evaluated in vitro inhibition potency of human drugs CLO and DEX on selected CYP450-mediated reactions in hepatic microsomes from juvenile rainbow trout. (acipimox.com)
- Oxygenated blood enters through the hepatic artery, and nutrient-rich blood leaves the liver through the portal vein. (goldrootherbs.com)
- The relationships between the level of skatole in backfat, the rate of skatole metabolism in isolated liver microsomes, hepatic cytochrome P450IIE1 content and mRNA levels were investigated in Large White ✕ Landrace (LW) and the Meishan ✕ Landrace (M) breeds. (uwe.ac.uk)
- Since tacrolimus is primarily metabolized by the liver, hepatic dysfunction may affect its metabolism. (bloodresearch.or.kr)
- Mays DC, Hilliard JB, Wong DD, Chambers MA, Park SS, Gelboin HV and Gerber N: Bioactivation of 8-methoxypsoralen and irreversible inactivation of cytochrome P-450 in mouse liver microsomes: Modification by monoclonal antibodies, inhibition of drug metabolism and distribution of covalent adducts. (spandidos-publications.com)
- Quercetin (an inhibitor of CYP2C8/3A4) was a less effective inhibitor producing 62 ± 22% inhibition in human liver microsomes and 54 ± 35% in hepatocytes. (aspetjournals.org)
- First, F ic successfully harmonized system-dependent CYP450 enzyme inhibition values (IC 50 ) obtained in human hepatocytes and human liver microsomes. (diva-portal.org)
- The inhibition of CHR on enzymatic activity of CYP1A2, CYP2A, CYP2C19, CYP2D6, CYP2E1, and CYP3A in rat liver microsome was also investigated. (biomedcentral.com)
- MicroConstants offers a range of services to evaluate the potential for drug-drug interactions, including cytochrome P450 (CYP450) induction studies, CYP/UGT inhibition studies, and CYP/UGT reaction phenotyping. (microconstants.com)
- CYP450 inhibition studies are conducted with human liver microsomes, FDA-accepted probe substrates, and control inhibitors. (microconstants.com)
- Both IC 50 and K i values can be determined, and the pre-incubation of the test article with microsomes and NADPH is used to assess time-dependent inhibition. (microconstants.com)
- The thermodynamic inhibition constant, Ki, is the recommended parameter by the FDA for investigating the clinical potential for CYP450-related DDI. (quintaradiscovery.com)
- Selected potent 11β-HSD1 inhibitors show moderate metabolic stability upon incubation with human liver microsomes and weak inhibition of human CYP450 enzymes. (ox.ac.uk)
- For example, if it is learned early in drug development that a molecule is not a substrate for CYP450 3A4 or that this pathway represents only a minor contribution to overall metabolism, then concern is lessened or eliminated for possible inhibition of 3A4 metabolism by drugs such as ketoconazole and erythromycin or possible induction of metabolism by drugs such as rifampin and anticonvulsants. (pharmacistspharmajournal.org)
- For example, quinidine and ketoconazole are relatively selective inhibitors of 2D6 and 3A4, respectively, at concentrations below 1 micromolar, but both will also inhibit other CYP450 enzymes at higher concentrations, an inhibition that is not known to be clinically ertinent. (pharmacistspharmajournal.org)
- Antibodies to specific CYP450 enzymes also can be used to attempt elective inhibition of metabolic pathways, but at present this approach is limited by lack of wide commercial availability of the antibodies, incomplete haracterization of their selectivity, and high laboratory-to-laboratory variation for antibody inhibition results in comparison to chemical inhibitors. (pharmacistspharmajournal.org)
- Here we report on the pharmacokinetics of JPC-3210 in mice and monkeys and the results of in vitro screening assays, including the inhibition of cytochrome P450 (CYP450) isozymes. (elsevier.com)
- To explore the potential for mechanism-based inhibition, we preincubated INH with microsomes from human livers in the presence of an NADPH-generating system before adding tolbutamide as a substrate probe. (tropicalmoka.com)
- Medications that interact with the CYP450 system typically do so in one of three ways: 1) through inhibition, 2) through induction, or 3) by acting as a substrate. (hivguidelines.org)
- Although inhibition is usually reversible, irreversible inhibition of CYP450 can occur, requiring new CYP450 enzyme to be synthesized to overcome the inhibition. (hivguidelines.org)
- Discussion There are a large number of studies of the inhibition of CYP450 by pharmaceuticals in mammalian in vitro models. (acipimox.com)
- In vitro CYP inhibition studies are often recommended to evaluate the potential of the proposed metabolite product to inhibit the human liver microsomal CYP enzymes as compared to the parent product. (camargopharma.com)
- Human microsome pools are fully characterized (K m and V max ) according to GLP standards for major cytochrome P450 activities and select Phase II enzymes using FDA recommended substrates (Tables 2-3). (thermofisher.com)
- Incubation of new drug candidates with substrates/inhibitors of specific cytochrome P450 isoforms with human liver microsomes and hepatocytes is a powerful tool in the characterization of their P450-mediated metabolism. (aspetjournals.org)
- Alternatively, we can use recombinant CYP450 enzymes with fluorogenic probe substrates in screening assays. (microconstants.com)
- Moreover, M13 exhibited higher conversion of substrates than M15 and CYP450 BM3 enzymes. (biomedcentral.com)
- This study was conducted using liquid chromatography-tandem mass spectroscopy (LC-MS/MS) using probe substrates using human liver microsomes against CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4(Midazolam) and CYP3A4 (Testosteron). (readbyqxmd.com)
- Using a cocktail probe of CYP450 isoform-specific substrates and their metabolites, we then carried out in vitro enzymatic studies in liver microsomal incubation systems via ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Finally, we verified our results at the messenger ribonucleic acid (mRNA) and protein level through quantitative real-time polymerase chain reaction (RT-qPCR), western blotting, and immunohistochemical detection. (biomedcentral.com)
- A sensitive and specific liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for simultaneous determination of seven metabolites of CYP450 model substrates (acetaminophen, 4-hydroxytolbutamide, 4'-hydroxymephenytoin, 1-hydroxybufuralol, 6-hydroxychlorzoxazone. (edu.pl)
- These metabolites can inhibit or deplete endogenous enzymatic and nonenzymatic antioxidants, cause oxidative stress, and lead to liver cell apoptosis and liver lipid peroxidation [ 4 ]. (hindawi.com)
- Ivermectin is metabolized in the liver, and ivermectin and/or its metabolites are excreted almost exclusively in the feces over an estimated 12 days, with less than 1% of the administered dose excreted in the urine. (nih.gov)
- For enterocyte CYP450 metabolism, the overall metabolic efficiency for the conversion to their active oxon metabolites was approximately 5-fold greater for CPF than DZN. (cdc.gov)
- Regioselective glucuronidation by UDP-glucuronosyltransferases (UGTs) and liver uptake by organic anion transporting polypeptides (OATPs) of luteolin and consequent glucuronidation metabolites were studied. (bvsalud.org)
- Luteolin-3'-O-glucuronide (L-3'-G) and luteolin-7-O-glucuronide (L-7-G) were the major metabolites in human liver microsomes. (bvsalud.org)
- To be able to investigate CYP450 stability in microsomes prepared from these tissues, a highly sensitive and rapid HPLC-MS/MS method for the simultaneous determination of six CYP450 metabolites in incubation medium was developed and validated. (springer.com)
- 1. Assessing the metabolism of a test drug The most mature technology for the study in vitro of drug metabolism (enzymes involved, metabolites formed, and potential inhibitors) is associated with the set of enzymes contained in the cytochrome CYP450 superfamily. (pharmacistspharmajournal.org)
- This study investigated the enzyme kinetics and the main CYP450 isozyme(s) involved in metabolism of (+)-praeruptorin A (dPA), an AP with significant cardio-protective activities, in human liver microsomes (HLMs) using ultra high-performance liquid chromatography coupled with a hybrid quadrupole-linear ion trap mass spectrometry (UHPLC-QT-MS/MS). dPA produced 6 metabolites via hydrolysis (M1-M3), oxidation (M4-M6), and hydrolysis followed by acyl migration (M2 or M3). (umac.mo)
- For metabolite products that have never been dosed orally (metabolites normally generated from the parent compound in the liver), intestinal microsome studies provide valuable information regarding the metabolism of the metabolite product at the gut wall during the absorption process. (camargopharma.com)
- These results suggested that psoralen and isopsoralen are modest hepatotoxic agents, as their reactive metabolites could be deactivated by H 2 O and GSH in the liver, which partly contributes to the ingestion of psoralen-containing fruits and vegetables being safe. (mdpi.com)
- We studied biotransformation of GBR12909 in human liver microsomes ( n = 4), human hepatocytes, and microsomes containing cDNA-expressed human P450 isoforms with GBR12909 concentrations within the range of steady-state plasma concentrations detected in healthy volunteers. (aspetjournals.org)
- In this study, the effects of triptolide on the six main CYP450 isoforms (1A2, 2C9, 2C19, 2D6, 2E1, and 3A) were investigated both in vivo and in vitro. (biomedcentral.com)
- In case of the CYP450 isoforms 3A, 2C9, 2C19, and 2E1, the in vitro metabolic study demonstrated a decrease in the substrate metabolic rate, metabolite production rate, and Vmax, with an increase in the Km value, compared with that observed in the control group. (biomedcentral.com)
- This study suggests that TP can cause hepatotoxicity by reducing the substrate affinity, activity, and expression at the transcriptional and protein levels of the CYP450 isoforms 3A, 2C9, 2C19, and 2E1. (biomedcentral.com)
- Incubation of test compounds with individual CYP450 isoforms. (qdibio.com)
- Incubation of test compound with human liver microsomes in the presence of specific inhibitors for each of the major CYP450 isoforms. (qdibio.com)
- Therefore, we studied the inhibitory effect of chloramphenicol on the activities of the major CYP isoforms in human liver microsomes and cDNA-expressed CYPs, using selective marker reactions to clarify the mechanism underlying the drug-drug interactions of chloramphenicol. (tropicalmoka.com)
- Skatole metabolism by liver microsomes was inhibited by diallyl sulphide, a specific inhibitor of cytochrome P450IIE1 but not by inhibitors of other P450 isoforms. (uwe.ac.uk)
- GBR12909 was metabolized by human liver microsomes, hepatocytes, and cDNA-expressed human P450s to a single metabolite. (aspetjournals.org)
- Ketoconazole, a selective inhibitor of CYP3A, reduced GBR12909 biotransformation in human liver microsomes and primary hepatocytes by 92 ± 2 and 92.4 ± 0.4%, respectively. (aspetjournals.org)
- Other P450 selective inhibitors did not decrease GBR12909 biotransformation more than 29% in either human liver microsomes or hepatocytes with the exception of chlorzoxazone (CYP2E1), which inhibited GBR12909 biotransformation by 71.4 ± 18.5% in primary human hepatocytes. (aspetjournals.org)
- Alcoholic liver disease is a result of complex pathophysiological events involving various types of cells, such as neutrophils, endothelial cells, Kupffer cells, and hepatocytes, and a variety of injurious factors such as endotoxin, oxidative stress, cytokines, and proteases 6 . (e-sciencecentral.org)
- The organ consists of liver cells called hepatocytes, which are grouped into lobules, who are then grouped into lobes. (goldrootherbs.com)
- Medications used in antiretroviral therapy, especially the non-nucleoside reverse transcriptase inhibitors (NNRTIs) and the protease inhibitors (PIs), are metabolized via the cytochrome P450 enzyme system (CYP450). (hivguidelines.org)
- Determine potential of selected CYP enzymes (1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4) involved in the metabolism of the test article (one concentration) using human liver microsomes + specific CYP-isoform inhibitors with t=0, 30 and 60 min. (qdibio.com)
- In vitro rat liver microsomal model was employed to elucidate the inhibitory effect of CHR on CYP1A2, CYP2A, CYP2C19, CYP2D6, CYP2E1, and CYP3A. (biomedcentral.com)
- For therapeutic agents that undergo extensive first-pass metabolism by CYP3A in the gut wall and liver, the reduction in serum concentrations of object drugs by enzyme inducers (precipitant drugs) can be profound. (podiatrytoday.com)
- In vitro studies using human liver microsomes and recombinant CYP450 enzymes have shown that ivermectin is primarily metabolized by CYP3A4. (nih.gov)
- The findings of in vitro studies using human liver microsomes suggest that clinically relevant concentrations of ivermectin do not significantly inhibit the metabolizing activities of CYP3A4, CYP2D6, CYP2C9, CYP1A2, and CYP2E1. (nih.gov)
- Xanthotoxin possesses the ability to inhibit mechanism‑based cytochrome P450 (CYP450)‑mediated activities in rats and mice. (spandidos-publications.com)
- 4 Limonoids extracted from Citrus reticulata Blanco exhibited significant growth-inhibitory effects at high concentrations (100mcg/mL) against human breast cancer cell lines (MCF-7), but did not inhibit leukemia (HL-60), ovary (SKOV-3), cervix (HeLa), stomach (NCI-SNU-1), or liver (Hep G2) cancer cells lines. (sigmaaldrich.com)
- Drugs that inhibit the CYP450 enzyme system generally lead to decreased rates of metabolism of other drugs metabolized by the same enzyme, resulting in higher drug levels and increased potential for toxicity. (hivguidelines.org)
- The presence of pharmaceuticals in the aquatic environment can induce and/or inhibit CYP450 activity in fish and thus modify enzymatic pathways mediated by CYP450 and cause unfavorable physiological effects and toxicity (Laville et al. (acipimox.com)
- Yamazaki H, Inoue K, Turvy CG, Guengerich FP, Shimada T. Effects of freezing, thawing, and storage of human liver samples on the microsomal contents and activities of cytochrome p450 enzymes. (springer.com)
- Preservation of various microsomal drug metabolizing components in tissue preparations from the livers, lungs and small intestines of rodents. (springer.com)
- All of the CYP450 enzymes are collected in the microsomal fraction. (pharmacistspharmajournal.org)
- We have shown that the rate of skatole metabolism by liver microsomes was proportional to the microsomal P450IIE1 content. (uwe.ac.uk)
- in vitro experiments with rat and human liver microsomes suggest that the CYP450 enzyme CYP2E1 hydroxylates indole into indoxyl. (wikipedia.org)
- Further studies revealed that taraxasterol significantly inhibited the ethanol-induced upregulation of CYP2E1, increased the ethanol-induced downregulation of Nrf2 and HO-1, and inhibited the degradation of inhibitory kappa B α (I κ B α ) and the expression level of NF- κ B p65 in liver tissues of ethanol-induced mice. (hindawi.com)
- These findings suggest that taraxasterol possesses the potential protective effects against ethanol-induced liver injury in mice by exerting antioxidative stress and anti-inflammatory response via CYP2E1/Nrf2/HO-1 and NF- κ B signaling pathways. (hindawi.com)
- The liver microsome CYP2E1 protein was detected using Western blot. (medsci.org)
- The resulting high level of CYP2E1 may induce oxidative stress and cause liver damage. (medsci.org)
- CYP1A1 is associated with polycyclic aromatic hydrocarbon-mediated carcinogenesis and CYP2E1 with liver damage by oxidative stress. (ovid.com)
- Studies of enzyme kinetics and binding with rat liver microsomes and supersomes® were carried out to determine whether HA is a substrate of CYP1A1 and/or CYP2E1. (ovid.com)
- Furthermore, HA is consumed in the presence of CYP2E1-induced microsomes and supersomes, as determined by o-phtalaldehyde complexes with HA by HPLC. (ovid.com)
- Glazier A.P., Kokwaro G.O., Edwards G. (1993): Possible isozyme-specific effects of experimental malaria with Plasmodium berghei on cytochrome P450 activity in rat liver microsomes. (springer.com)
- Effects of freezing , thawing, and storing human liver microsomes on cytochrome P450 activity. (springer.com)
- The histopathological changes of liver tissues were observed by hematoxylin and eosin (H&E) staining. (hindawi.com)
- Histopathological evidence showed the changes of liver tissues in terms of structure, size and tight arrangement. (medsci.org)
- However, before microsomes are prepared, tissues can be stored for a long time. (springer.com)
- Primary metabolism of many drugs is performed by the cytochrome P450 (CYP450) enzymes, a group of oxidative/dealkylating enzymes localized in the microsomes of many tissues, but primarily in the intestines and liver. (testcatalog.org)
- Cytochrome P450 and Phase II enzymes tested in Gibco human microsome pools. (thermofisher.com)
- When metabolism was compared per nmol P450 (nmol/min/nmol P450), the Vmax was approximately 3 and approximately 2 times higher in enterocytes than liver microsomes for CPF-oxon and TCP, respectively. (cdc.gov)
- At an early stage of drug development, rat liver microsomes (RLMs) with specific cytochrome P450 (CYP450) activity were employed as an approach for the investigation of drug metabolism [ 8 , 9 ]. (hindawi.com)
- Histamine (HA) may bind to cytochrome P450 (CYP450) in rat liver microsomes. (ovid.com)
- Cytochrome P450 (CYP450) and 5'-diphosphate glucuronosyltransferases (UGT) are the two major families of drug-metabolizing enzymes in the human liver microsome (HLM). (bvsalud.org)
- We used the Bacillus megaterium cytochrome P450 BM3 (CYP450 BM3) and its variants namely mutant 13 (M13) and mutant 15 (M15) for the hydroxylation of diverse class of flavonoids. (biomedcentral.com)
- CYP450 BM3 is a class II P450 enzyme that consists of natural fusion between heme-Fe-dependent monooxygenase domain and the electron transfer flavin mononucleotide (FMN)/flavin adenine dinucleotide (FAD) reductase domain in a single continuous 119 - kDa polypeptide. (biomedcentral.com)
- Microsomes are an ideal medium to investigate cytochrome P450 (CYP450) enzyme-mediated drug metabolism. (springer.com)
- Compounds begin to break down in the body by a family of enzymes in the liver called the Cytochrome P450 system. (medicilon.com)
- Cytochrome P450 (CYP450) is a large family of heme-containing enzymes, which catalyse a variety of metabolic reactions, such as oxidation, reduction, hydroxylation and dealkylation [ 1 , 2 ]. (ijpsonline.com)
- AIMS: The study aimed to identify the specific human cytochrome P450 (CYP450) enzymes involved in the metabolism of artemisinin. (isharonline.org)
- For those unfamiliar with the functions of the CYP450 enzymes, CYP450 stands for the Cytochrome P450 enzymes. (naturalblaze.com)
- In humans, a subset of Cytochrome P450 (CYP450) microsome-bound ω-hydroxylases (termed Cytochrome P450 omega hydroxylases) metabolize arachidonic acid (also known as eicosatetraenoic acid) to 20-hydroxyeicosatetreaneoic acid (20-HETE). (wikipedia.org)
- This study was conducted to examine the involvement of cytochrome P450 (CYP450) and the flavin-containing monooxygenase (FMO) in the sulphoxidation of ethyl methyl sulphide. (naver.com)
- Identification of cytochrome P450 isoenzymes involved in metabolism of (+)-praeruptorin A, a calcium channel blocker, by human liver microsomes using ultra high-performance liquid chromatography coupl[J]. JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS,2013,77:175-188. (umac.mo)
- 9 ] found that coadministration of grapefruit juice with artemether (150 mg/kg) eliminated eggs and granulomatous reactions and achieved complete protection of the host from damage induced by schistosomal infection because of the inhibitory effects of grapefruit juice on CYP450 and cyt b5. (biomedcentral.com)
- The CYP450 enzymes retain their activity for many years in microsomes or whole liver stored at low temperature (e.g., -70o C). Cofactor requirements for CYP450-mediated reactions are well characterized, consisting primarily of a redox sustaining system such as NADPH. (pharmacistspharmajournal.org)
- It seems intended to educate medical students about CYP450 enzymes in relation to drug metabolism and adverse drug reactions. (meboblog.com)
- Studies on trout have suggested DEX induction of 3-cyano-7-ethoxycoumarin metabolism, a reaction used to estimate mammalian CYP1A2 activity, but have not shown it to significantly affect CYP450-mediated reactions in killifish (Fundulus heteroclitus) (Smith and Wilson, 2010) and grass carp (Ctenopharyngodon idellus) (Li et al. (acipimox.com)
- Further, quinine produced robust dose-dependent oxidative stress in human erythrocytes in the presence of microsomes. (biomedcentral.com)
- Accumulated evidence has demonstrated that oxidative stress, abnormal cytokine production, especially tumor necrosis factor (TNF), and steatosis play important etiological roles in the pathogenesis of alcoholic liver disease. (e-sciencecentral.org)
- Chlorpyrifos (CPF) and diazinon (DZN) are organophosphate (OP) insecticides, and their toxicity is mediated through CYP450 metabolism to CPF-oxon and DZN-oxon, respectively. (cdc.gov)
- The aim of the present study was to predict the effect of inter-individual and inter-ethnic human kinetic variation on the sensitivity towards acute liver toxicity of lasiocarpine in the Chinese and the Caucasian population, and to derive chemical specific adjustment factors (CSAFs) by integrating variation in the in vitro kinetic constants V max and K m , physiologically based kinetic (PBK) modelling and Monte Carlo simulation. (springer.com)
- These results indicate that when considering the formation of 7-GS-DHP the Caucasian population may be more sensitive towards acute liver toxicity of lasiocarpine, and further point out that the default safety factor of 3.16 for inter-individual human kinetic differences may not be sufficiently protective. (springer.com)
- I get excited about being right, about being at the forefront of this problem, about being able to tell people, "I told you so" when they realize that quinolone toxicity is a huge problem that is adversely affecting the lives of millions of people. (floxiehope.com)
- The objective of this study is to evaluate the protective effects of taraxasterol and its possible underlying mechanisms against ethanol-induced liver injury in mice. (hindawi.com)
- In addition, taraxasterol improved the liver histopathological changes in mice with ethanol-induced liver injury. (hindawi.com)
- CCl4 (a human hepatotoxin known to cause liver injury, cirrhosis, and cancer) was administered to mice for up to 16-wk as a classical model of liver cirrhosis. (xfibra.com)
- CYP450 enzymes are most abundant in the liver and induce metabolic activation of numerous xenobiotic compounds. (spandidos-publications.com)
- We elucidated that eriodictyol being produced from naringenin using recombinant CYP450 BM3 and its variants from B. megaterium , which shows an approach for the production of important hydroxylated compounds of various polyphenols that may span pharmaceutical industries. (biomedcentral.com)
- However, there have been no reports of either CYP450 BM3 wild type or mutant M13 and M15 modifying flavonoid groups of compounds to produce diverse hydroxylated products. (biomedcentral.com)
- We also offer optional addition of S9 fraction rat liver extracts to metabolically bioactivate genotoxins, which increases the number of mutagenic compounds detected by the Ames assays. (biotoxicity.com)
- CYP450 enzymes essentially make compounds more soluble so they can be excreted by the body. (goldrootherbs.com)
- Our therapeutic is designed to block a single posttranslational modification on one protein, a single event critical to liver scar tissue production and nonessential to other mechanistic processes. (xfibra.com)
- The M breed was shown to express high levels of the multidrug resistance protein in liver, and it is suggested that export of skatole from liver via this transport protein may be an additional factor regulating backfat skatole in M pigs, but not in the LW breed. (uwe.ac.uk)
- We provide liver subcellular fractions from a variety of tox species, including human, nonhuman primates (Cynomolgus Monkey and Rhesus Monkey), dog (Beagle), rat (Sprague-Dawley), mouse (CD-1), and trout (Oncorhynchus mykiss). (thermofisher.com)
- Relevant applications for liver subcellular fractions. (thermofisher.com)
- Microsomes are a subcellular fraction of tissue obtained by differential high-speed centrifugation. (pharmacistspharmajournal.org)
- The present study aimed to identify the similarities and differences in xanthotoxin metabolism in liver microsomes of 7 mammalian species, including human liver microsomes (HLM), Rhesus monkey liver microsomes (RMLM), Cynomolgus monkey liver microsomes (CMLM), Sprague Dawley rat liver microsomes (RLM), mouse liver microsomes (MLM), Dunkin Hartley guinea pig liver microsomes (PLM) and Beagle dog liver microsomes (DLM). (spandidos-publications.com)
- The correlation analysis involves a bank of liver microsomes from at least 10 donors. (microconstants.com)
- During studies to identify metabolic routes of elimination for an investigational new drug, microsomes from several donors should be used, either individually or pooled, to avoid reliance on microsomes that are deficient in one or more metabolic pathways, unless this is a specific objective of the study. (pharmacistspharmajournal.org)
- Studies in the isolated perfused rat liver. (springer.com)
- From the animal efficacy studies and using the FDA conversion Tables for human dosing, it is expected that a dose of 1mg (50 l) administered weekly should be effective in patients with chronic liver diseases. (xfibra.com)
- Liver microsomes are the most frequently used form of tissue preparations for in vitro drug metabolism studies. (quintaradiscovery.com)
- The connection to CYP450 enzymes and the adverse effects of psycho-pharmaceuticals has been documented in many different scientific studies. (naturalblaze.com)
- For example, liver microsomes and whole hepatocyte models are commonly used in ADME in vitro studies, both models contain metabolism enzymes such as CYP450 and UDP-glucuronosyltransferase (UGT). (coreinformatics.com)
- Detoxification of CPF and DZN is also mediated by CYP450 and A-esterase (A-EST) metabolism of CPF- and DZN-oxon, resulting in the formation of trichloropyridinol (TCP) and 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMHP), respectively. (cdc.gov)
- More than the physicochemical properties, the composition of NPs (organic, inorganic) dramatically influenced the detoxification function of the liver. (biopredic.com)
- Many people associate the liver with filtration/detoxification activities. (goldrootherbs.com)
- You might be tempted to think of these enzymes as confined to the liver and its detoxification activities. (goldrootherbs.com)
- Arterial blood samples (2 ml) were collected in plastic heparinized syringes after induction of anesthesia (T0), immediately after removal of the native liver (T1), 15 min (T2) and 30 min (T2′) later, just before the unclamping of the newly transplanted liver (T3), and finally 60 (T4) and 120 min (T5) after reperfusion of the new liver. (asahq.org)