Drug-metabolizing cytochrome P450 (CYPs) enzymes are portrayed within the liver, in addition to in extrahepatic tissues like the brain. inhibitors considerably elevated sleep-time (1.8- to 2-collapse) and mind propofol amounts, whilst having no influence on plasma propofol amounts. A week of nicotine treatment can induce the appearance of human brain, however, not hepatic, CYP2B, which induction decreased propofol sleep moments by 2.5-fold. This decrease was reversed within a dose-dependent way by i.c.v. shots of inhibitor. Rest moments correlated with human brain ((Albores contribution of CNS fat burning capacity in the current presence of hepatic fat burning capacity and the passing of peripheral metabolites in to the human brain. Recent advances inside our ability to measure the appearance and activity of extrahepatic CYPs indicate that rat human brain CYPs are energetic and fat burning capacity by these CYPs could be changed locally in the mind (Miksys and Tyndale, 2009). This permits us, ...
Liver microsomes from 3-methylcholanthrene-pretreated Long-Evans rats catalyzed the 2- and the 4-hydroxylation of biphenyl and the O-deethylation of ethoxyresorufin, sustained by either NADPH or cumene hydroperoxide. In contrast, the liver microsomes from corn oil- or phenobarbital-pretreated rats catalyzed the NADPH- or cumene hydroperoxide-sustained 4-hydroxylation of biphenyl, but the rates of 2-hydroxylation or ethoxyresorufin deethylation were negligible. A monooxygenase system reconstituted with partially purified NADPH-cytochrome c reductase and cytochrome P-448 catalyzed NADPH-supported biphenyl 2- and 4-hydroxylation and ethoxyresorufin deethylation. A monooxygenase system reconstituted with the reductase and cytochrome P-450 catalyzed NADPH-supported biphenyl 4-hydroxylation but exhibited negligible 2-hydroxylation or ethoxyresorufin deethylation activites. Solubilized cytochrome P-448 catalyzed biphenyl 2- and 4-hydroxylation and ethoxyresorufin deethylation sustained by cumene ...
1. Cimetidine pretreatment of male Sprague-Dawley rats caused a significant increase in the specific content of total hepatic cytochrome P-450, supporting the hypothesis that this H2-receptor antagonist has monooxygenase induction effects. 2. Quantitative ultrastructural studies of liver of cimetidine-pretreated animals also supported this hypothesis in showing a significant proliferation of smooth endoplasmic reticulum. These ultrastructural changes were qualitatively similar to those produced by treatment of rats with phenobarbital, a well-characterized monooxygenase-inducing agent whose effects were studied for comparative purposes. 3. Competitive inhibition of metoprolol αhydroxylation by cimetidine in liver microsomes prepared from untreated animals (Ki = 18.8 μM) was also demonstrated. 4. These results allowed testing of the hypothesis (Burnet el al. 1986) that inhibition of a defined monooxygenase should lead to induction of the synthesis of the relevant cytochrome P-450 isozyme. 5. The ...
Author: Garda, H. A. et al.; Genre: Journal Article; Published in Print: 1994-12-07; Keywords: CYTOCHROME P450 LM2; SUBSTRATE BINDING; MICROHETEROGENEITY; MULTIPLICITY|br/|; Title: Heterogeneity in rabbit liver cytochrome P-450 LM2 observed by cation exchange HPLC: Partial biochemical characterization of the two major LM2 subfractions
The isolation and purification of two major phenobarbitone-induced hepatic cytochromes P-450 from male Wistar rats is described. These forms (designated cytochromes P-450 B1 and P-450 B2) were extensively characterised and structurally and functionally compared to two other homogeneous isoenzymic forms, cytochromes P-452 (clofibrate-induced) and cytochrome P-447 (BNF-induced). These characterisation studies (including catalytic, immunological, physical and spectral analysis) indicated that all four isoenzymes were distinct, unique hemoproteins. The above characterisation was extended towards the induction profiles of these hemoproteins in hepatic and renal microsomes, following single dose xenobiotic pretreatment. Of primary interest was the immunoquantitation data which revealed the presence of cytochrome P-452 as a major constitutive isoenzyme. This data in conjunction with the metabolic data also indicated that xenobiotic induction of cytochromes P-450 was both a specific and precise event. ...
(S,S)-3-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride [(-)-OSU6162] is a weak dopamine D2 receptor modulator that possesses potential for the treatment of levodopa (L-DOPA)-induced dyskinesias in patients with Parkinsons disease. In this report, incubations with human liver microsomes revealed that (-)-OSU6162 is selectively metabolized via N-dealkylation to yield N-depropyl (-)-OSU6162. Kinetics evidence is presented that the N-depropylation of (-)-OSU6162 in human hepatic microsomes is mediated by multiple cytochrome p450 (p450) enzymes, in particular CYP2D6. This hypothesis is borne out by several lines of in vitro evidence; 1). incubations of (-)-OSU6162 (5 micro M) with hepatic microsomes from a panel of human donors showed that (-)-OSU6162 N-depropylase activity correlated well with CYP2D6-catalyzed dextromethorphan O-demethylase activity but not with other p450 enzyme-specific activities; 2). quinidine, a CYP2D6-specific inhibitor, inhibited (-)-OSU6162 N-depropylation, whereas
hepatic microsomal mixed function oxidase system의 중추인 cytochrome p-450은 주위환경, 약물, 식이 및 영양 상태에따라 활성이 변화하는것으로 알려져있다. 또한 이 효소계를 통하여 대사되는 2-acetylaminofluorene은 guinea pig를 제외한 모든 동물에서 간암을 일으키는 물질이라는것이 밝혀져서 연구의 대상이 되고있다. 최근 cholesterol은 성인병에 있어 그 원인 인자로서 중요성이 알려지고 있으며 cytochrome p-450과 b_(5)와의 연관성이 보고된바있다. 한편 인삼은 항암작용, 대사촉진, 간조직에서의 해독작용등 여러가지 기능이 보고되어 있다. 이에 저자는 cholesterol을 투여한 흰쥐에서 hepatic microsomal cytochrome p-450 및 b_(5)의 활성에대한 영향과 2-AAF의 ring-hydroxylation과 N-hydroxylation의 변화를 관찰하고, cholesterol과 인삼을 통시에 투여한 군과 비교관찰하여 다음과 같은 결론을 얻었다. 1) 정상 ...
1. We have constructed a full-length human liver cytochrome P450IIA cDNA from a partial-length clone by oligonucleotide-directed mutagenesis, and subcloned it into the monkey kidney (COS-7) cell expression vector, pSVL. 2. The cDNA encodes a 49 kDa protein with coumarin 7-hydroxylase (COH) activity which cross-reacts with antisera to the mouse cytochrome P-450 isoenzyme responsible for COH activity and comigrates with a human liver microsomal protein. 3. Western blot analysis of a panel of human livers indicates that the level of the 49 kDa protein, detected using antisera to either the mouse COH P-450 or rat P450IIA1 protein, correlates very highly with COH activity. 4. Antisera to the rat P450IIA1 protein can inhibit COH activity in human liver microsomes. Taken together, these data indicate that a member of the P450IIA subfamily is responsible for most, if not all, of the COH activity in human liver. ...
Studies were carried out on the developmental profile of PB-cytochrome P-450 and cytochrome P-448-dependent mixed-function oxidase activities in the foetal and neonatal rat. PB-Cytochrome P-450 activity, as examplified by benzphetamine N-demethylase was low at birth but increased with age. In contrast, cytochrome P-448 activity, as exemplified by ethoxyresorufin 0-deethylase (EROD) and biphenyl 2-hydroxylase, was higher in the neonate, reaching maximum levels at about two weeks postpartum and decreased with age. Cytochrome P-448 inducibility by 3-methylcholanthrene was low at birth and increased with age. Investigations were also carried out on the induction of cytochrome P-448, as measured by the 0-deethylation of ethoxyresorufin, by carcinogens and several other xenobiotics in hepatic and extrahepatic tissues of the adult male rat. EROD activity was highest in the liver, followed by the kidney , lung, in the untreated animal; activity was not detectable in the heart and the brain. Treatment ...
Interindividual variations in the level and activity of cytochrome P-450 enzymes were investigated in the liver microsomes of 30 Japanese and 30 Caucasian patients. The P-450 enzymes used in this study included P-450 1A2, 2A6, 2B6, 2C, 2D6, 2E1 and 3A, and the monooxygenase activities determined were 13 typical P-450 substrates and 9 procarcinogens. Although the total P-450 content was higher in Caucasian (mean, 0.43 nmol/mg of protein) than in Japanese populations (mean, 0.26 nmol/mg of protein), the relative levels (percent of total P-450) of individual forms of P-450 determined immunochemically were not very different except that P-450 2A6 and 2B6 levels were higher in the Caucasians. About 70% of liver P-450 could be accounted for by P-450 1A2, 2A6, 2B6, 2C, 2D6, 2E1 and 3A proteins, and P-450 3A (about 30% of total P-450) and 2C (about 20%) enzymes were found to be the major forms. Considerable levels of P-450 1A2 (about 13%) and 2E1 (about 7%) could be determined, whereas the P-450 2A6 ...
Interindividual variations in the level and activity of cytochrome P-450 enzymes were investigated in the liver microsomes of 30 Japanese and 30 Caucasian patients. The P-450 enzymes used in this study included P-450 1A2, 2A6, 2B6, 2C, 2D6, 2E1 and 3A, and the monooxygenase activities determined were 13 typical P-450 substrates and 9 procarcinogens. Although the total P-450 content was higher in Caucasian (mean, 0.43 nmol/mg of protein) than in Japanese populations (mean, 0.26 nmol/mg of protein), the relative levels (percent of total P-450) of individual forms of P-450 determined immunochemically were not very different except that P-450 2A6 and 2B6 levels were higher in the Caucasians. About 70% of liver P-450 could be accounted for by P-450 1A2, 2A6, 2B6, 2C, 2D6, 2E1 and 3A proteins, and P-450 3A (about 30% of total P-450) and 2C (about 20%) enzymes were found to be the major forms. Considerable levels of P-450 1A2 (about 13%) and 2E1 (about 7%) could be determined, whereas the P-450 2A6 ...
Chronic treatment of rats with the naturally occurring androgen, testosterone, leads to hypertension and cardiovascular disease. This effect is believed to be mediated through the adrenal gland and in particular by action on the steroid 11 beta-hydroxylase enzyme system. To study the possible mechanism of this effect, the enzyme system was examined at several time periods up to the time that hypertension develops. Rats were treated with testosterone (10 mg/day) for 3, 7, 21, and 42 days. Levels of cytochrome P-450(11) beta enzyme and messenger RNA (mRNA) were determined as well as 11 beta-hydroxylase enzyme activity. A significant decrease in enzyme activity was observed after 3 days of treatment. This correlates with a profound decrease in the level of cytochrome P-450(11) beta enzyme as determined by Western blot analysis. A large decrease in cytochrome P-450(11) beta mRNA was also observed after 3 days of treatment. All three parameters remained low throughout the treatment period. The ...
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.
Aggregates were formed when clear supernatants from hepatic microsomes that had been treated with steapsin were desalted and concentrated. These aggregates contain large numbers of uniform tubular elements. These structures resemble microtubules seen in many cells but differ in their substructure. The aggregates were rich in cytochrome P-420. Unlike soluble cytochrome P-420, the cytochrome P-420 contained in the aggregates combines with drugs to give the characteristic difference spectra normally seen only with cytochrome P-450 contained in intact microsomes. ...
Rabbit anti-human cytochrome P450 enzyme CYP2D6 (polyclonal antibody). O-demethylation of xenobiotics, CYP2D6 is involved in the metabolism and elimination of approximately 25% of clinically used drugs in humans1. Primarily expressed in the liver and areas of the CNS. CYP2D1 and CYP2D4 have a similar function in rats2.. CODE NUMBER: RT01.. QUANTITY: 0.1 mL.. SPECIFICITY: Reacts with human cytochrome P450 enzyme CYP2D6 in hepatic microsomal fraction. No cross-reactivity with other cytochrome P450 enzymes.. IMMUNOGEN: Synthetic peptide.. SUGGESTED APPLICATIONS: Western blot, immunohistochemistry on frozen and formaldehyde treated sections. Optimal working dilutions must be determined by end user.. SPECIES REACTIVITY: Human.. FORMAT: Rabbit antiserum.. PRESENTATION: Liquid. No preservatives.. STORAGE/HANDLING: Maintain at -20°C in undiluted aliquots for up to 12 months. Avoid repeated freeze/thaw cycles.. For research use only; not for use in diagnostic procedures. Not for human or animal ...
Rabbit anti-rat cytochrome P450 enzymes CYP1A1 and CYP1A2 (polyclonal antibody). Involved in metabolism of xenobiotics, drugs and polyunsaturated fatty acids. Implicated in metabolism of some polycyclic hydrocarbons to carcinogenic intermediates. CODE NUMBER: R1V.. QUANTITY: 0.1 mL.. SPECIFICITY: Reacts with rat cytochrome P450 enzymes CYP1A1 and CYP1A2 in hepatic microsomal fraction. No cross-reactivity with other cytochrome P450 enzymes.. IMMUNOGEN: Synthetic peptide.. SUGGESTED APPLICATIONS: Western blot: useful for the simultaneous detection of rat CYP1A1 (57 kDa) and CYP1A2 (54 kDa), which can be separated by SDS-polyacrylamide electrophoresis. Immunohistochemistry on frozen and formaldehyde treated sections. Optimal working dilutions must be determined by end user.. SPECIES REACTIVITY: Rat.. FORMAT: Rabbit antiserum.. PRESENTATION: Liquid. No preservatives.. STORAGE/HANDLING: Maintain at -20°C in undiluted aliquots for up to 12 months. Avoid repeated freeze/thaw cycles.. For research use ...
Steroids are the most widely marketed products by the pharmaceutical industry after antibiotics. Steroid hydroxylation is one of the most important functionalizations because their derivatives enable a higher biological activity compared to their less polar non-hydroxylated analogs. Bacterial cytochrome P450s constitute promising biocatalysts for steroid hydroxylation due to their high expression level in common workhorses like Escherichia coli. However, they often suffer from wrong or insufficient regio- and/or stereoselectivity, low activity, narrow substrate range as well as insufficient thermostability, which hampers their industrial application. Fortunately, these problems can be generally solved by protein engineering based on directed evolution and rational design. In this work, an overview of recent developments on the engineering of bacterial cytochrome P450s for steroid hydroxylation is presented.
Sigma-Aldrich offers abstracts and full-text articles by [Alena Vanduchova, Veronika Tomankova, Pavel Anzenbacher, Eva Anzenbacherova].
The endocannabinoid system is important for many physiological and pathological processes, but its role in the regulation of liver cytochromes P450 (CYPs) is still unknown.We studied the influence of the endocannabinoid oleamide on rat and human liver CYPs. Oleamide was administered i.p. to rats at doses of 0.1, 1 and 10 mg/kg/day for 7 days. The content and activity of key CYPs was evaluated in rat liver microsomes. Moreover, its interactions with nuclear receptors regulating CYP genes and serum levels of their ligands (prolactin, corticosterone, and free triiodothyronine) were tested in vitro CYP inhibition assays. Decreased protein levels and metabolic activities of CYP1A2, CYP2B, and CYP2C11 along with a drop in metabolic activity of CYP2D2 were observed in animals treated with oleamide (10 mg/kg/day). The activities of CYP2C6, CYP2A, and CYP3A and the levels of hormones were not altered. In vitro, oleamide exhibited a weak inhibition of rat CYP1A2, CYP2D2, and CYP2C6. The activities of rat ...
Buy our Recombinant Human Cytochrome P450 2A6 protein. Ab114776 is a protein fragment produced in Wheat germ and has been validated in WB, ELISA, SDS-PAGE…
Buy our Recombinant Human Cytochrome P450 3A4 protein. Ab114327 is a full length protein produced in Wheat germ and has been validated in WB, ELISA, SDS-PAGE…
With monoclonal antibodies against cytochrome P-450(5) and P-450(4,5,6), 52 and 54 kDa bands are visualized in microsomes from proximal as well as distal human small intestine. These bands most probably correspond to cytochrome P-450(5) and P-450(4), respectively. This and several other cytochrome P …
In this study we present evidence that brain cells consume NO by a membrane-localized process that involves NADPH oxidation by CYPOR, a microsomal protein that transfers electrons from NADPH to an acceptor, classically a haem-containing cytochrome P450 [27]. Cytochrome P450 inhibitors decreased NO consumption by brain membranes, suggesting that reduction of these proteins by CYPOR underlies NO consumption.. Cytochrome P450s perform hydroxylation reactions which, in the brain, are involved in diverse functions including steroid hormone synthesis, cholesterol homoeostasis and vitamin, eicosanoid and xenobiotic metabolism [28,29]. Both CYPOR and several members of the cytochrome P450 family are expressed in brain, though at much lower levels than in the liver (1-10%; [30]). Interestingly, NO has been shown to bind and inhibit several cytochrome P450s [31,32], making them intriguing candidates for NO consumption by brain membranes. Indeed, the reductase domain of NOS is very similar to that of CYPOR ...
TY - JOUR. T1 - Induction of rat small intestinal cytochrome P-450 2J4. AU - Zhang, Qing Yu. AU - Ding, Xinxin. AU - Dunbar, Deborah. AU - Cao, Ling. AU - Kaminsky, Laurence S.. PY - 1999/10/13. Y1 - 1999/10/13. N2 - Cytochrome P-450 (CYP) 2J4 is a member of the recently identified CYP2J subfamily-part of the CYP superfamily-and is primarily expressed in rat small intestinal epithelium (enterocytes). Studies to determine small intestinal CYP2J4 inducibility by prototypic CYP inducers have been undertaken. Immunoblot analysis of enterocyte microsomes from rats treated with β- naphthoflavone, dexamethasone, or phenobarbital revealed unchanged, diminished, or slightly increased levels of CYP2J4 protein, respectively, relative to vehicle-treated rats, whereas rats treated with pyrazole (200 mg/kg) had 3- to 4-fold increased levels of CYP2J4. Pyrazole administration also increased CYP2J4 metabolic activity, as probed by retinoic acid formation from retina, approximately 3-fold, and the activity was ...
AIMS: To characterize potential mechanism-based inactivation (MBI) of major human drug-metabolizing cytochromes P450 (CYP) by monoamine oxidase (MAO) inhibitors, including the antitubercular drug isoniazid. METHODS: Human liver microsomal CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A activities were investigated following co- and preincubation with MAO inhibitors. Inactivation kinetic constants (KI and kinact) were determined where a significant preincubation effect was observed. Spectral studies were conducted to elucidate the mechanisms of inactivation. RESULTS: Hydrazine MAO inhibitors generally exhibited greater inhibition of CYP following preincubation, whereas this was less frequent for the propargylamines, and tranylcypromine and moclobemide. Phenelzine and isoniazid inactivated all CYP but were most potent toward CYP3A and CYP2C19. Respective inactivation kinetic constants (KI and kinact) for isoniazid were 48.6 µm and 0.042 min1 and 79.3 µm and 0.039 min1. Clorgyline was a selective ...
Graham, Kirsty, Sparagano, Olivier, Pérez de Léon, Adalberto, Bell-Sakyi, Lesley, Guerrero, F. and Finn, Robert (2012) Identification of Novel Cytochrome P450s in the Acari. In: 19th International Symposium on Microsomes and Drug Oxidations and 12th European ISSX Meeting, 17-21 June, 2012, Noordwijk aan Zee, the Netherlands. Full text not available from this repository. (Request a copy ...
Immunochemical properties of P-450HFLb purified from human fetal livers were investigated. P-450HFLb cross-reacted with antibodies to rat P-4501A1 but not with antibodies to CYP2A6, CYP2C9, CYP3A7 (P-450HFLa) and rat CYP2B1. In addition, P-450HFLb also cross-reacted with both monospecific antibodies to rat CYP1A1 and CYP1A2. However, P-450HFLb was shown to be an immunochemically distinct form of cytochrome P-450 from P-450PA (human CYP1A2). Immunoblot analysis of human fetal livers with the antibodies to P-450HFLb showed that P-450HFLb was expressed in all fetal livers studied although there appeared to be individual differences in the amounts of P-450HFLb expressed in fetal livers. The formation of mutagens from IQ (but not from AFB1) in fetal liver homogenates was inhibited by the antibodies to P-450HFLb in a dose dependent manner. These results suggest that P-450HFLb may be a form of human cytochrome P-450 classified into CYP1 gene family, and that the cytochrome P-450 is, in part, ...
The cytokine-mediated suppression of hepatic drug-metabolizing enzymes by inflammatory disease and the relief of this suppression by successful disease treatment have recently become an issue in the development of drug interaction labels for new biological products. This study examined the effects of the inflammatory cytokine interleukin-6 (IL-6) on drug-metabolizing enzymes in human hepatocyte culture and the abrogation of these effects by a monoclonal antibody directed against IL-6. Treatment of human hepatocytes with IL-6 (n = 9 donors) revealed pan-suppression of mRNA of 10 major cytochrome P450 isoenzymes, but with EC50 values that differed by isoenzyme. Some EC50 values were above the range of clinically relevant serum concentrations of IL-6. Marker activities for CYP1A2 and CYP3A4 enzyme were similarly suppressed by IL-6 in both freshly isolated and cryopreserved hepatocytes. IL-6 suppressed induction of CYP1A2 enzyme activity by omeprazole and CYP3A4 enzyme activity by rifampicin but ...
www.MOLUNA.de Cytochrome P-450 [4208648] - Major advances have been made in recent years in clarifying the molecular properties of the cytochrome P-450 system. These advances stem, in practical terms, from the generally recognized importance of cytochrome P-450 in the metabolism of drugs and in the bioactivation of xenobiotics to toxic products. The fascinating multiplicity and
Hepatic microsomal cytochrome P450s, which are involved in the metabolism of drugs, hormones, prostaglandins and fatty acids, change when animals develop diabetes. We studied changes in cytochrome P450 isozymes in both hepatic and renal microsomes of rats with diabetes caused by streptozocin, and co …
Semantic Scholar extracted view of [Effects of hepatoprotective agents containing phospholipids on cytochrome P-450-dependent antitoxic liver function during experimental toxic hepatitis]. by S. As et al.
The pharmaceutical industry is committed to market safer drugs with fewer side effects, predictable pharmacokinetic properties and quantifiable drug-drug interactions. There is an increasing need to develop robust, enhanced-throughput in vitro assays, which accurately extrapolate to humans. The major drug metabolizing human hepatic cytochrome P450s (CYPs; CYP1A2, 2C9, 2C19, 2D6 and 3A4) have been co-expressed functionally in Escherichia coli with human NADPH-cytochrome P450 reductase and validated as surrogates to their counterparts in human liver microsomes (HLM) with respect to their kinetic and inhibition properties. Using these recombinant enzymes, fully automated in vitro assays to assess CYP inhibition and determine the enzymology of drug oxidation have been developed and validated. IC50 values determined for a series of test compounds in HLM and recombinant CYPs were similar (r2 = 0.9, P , 0.001). There was a good correlation between the sum of individual CYP intrinsic clearance (Clint) ...
Domain combinations containing the Serine metabolism enzymes domain superfamily . Domain architectures illustrate each occurrence of the Serine metabolism enzymes domain superfamily.
hypothetical protein, flavoprotein-linked monooxygenase, microsomal monooxygenase, xenobiotic monooxygenase, 4-nitrophenol 2-hydroxylase, CPE1, Cyp2e, CYPIIE1, cytochrome P-450, cytochrome P450 2E1, cytochrome P450, 2e1, ethanol inducible, cytochrome P450-ALC, cytochrome P450 CYP2E1, cytochrome P450, family 2, subfamily e, polypeptide 1, cytochrome P-450-J, cytochrome P450-J, cytochrome P450RLM6, cytochrome P450 subfamily 2e1 (ethanol-inducible), cytochrome P450, subfamily 2E, polypeptide 1, cytochrome P450, subfamily IIE (ethanol-inducible), polypeptide 1, P450C2E, P450-J, P450RLM6, cyp2e1 ...
Polycyclic aromatic hydrocarbons (PAHs) are products of incomplete combustion that are commonly inhaled by workers in the dusty trades. Many PAHs are metabolized by cytochrome P-4501A1 (CYP1A1), which may facilitate excretion but may activate pulmonary carcinogens. PAHs also stimulate their own metabolism by inducing CYP1A1. Recent studies suggest that respirable coal dust exposure inhibits induct
Two 3-methylcholanthrene inducible cytochromes MC1 (mol. wt. 54500) and MC2 (mol. wt. 57000) were present at very low levels, MC2 mostly in the periportal region but also diffusely distributed throughout the lobule including some centrilobular cells, MC1 concentrated in the centrilobular region. The immunohistological localization of two major groups of glutathione transferases (GSTs) was also different. C type proteins (Yb Yb) and microsomal epoxide hydrolase (EH) , were concentrated around the central vein, whereas the B type proteins (Ya Yc) and cytochrome P450 reductase were distributed in a larger area of this region. Thus, the localization was different for some members of the same enzyme family, whilst similarities in the localization existed across the border of the families. ...
Protein domain dynamics and electron transfer chemistry are often associated, but real-time analysis of domain motion in enzyme-catalysed reactions and the elucidation of mechanistic schemes that relate these motions to the reaction chemistry are major challenges for biological catalysis research. Previously we suggested that reduction of human cytochrome P450 reductase with the reducing coenzyme NADPH is accompanied by major structural re-orientation of the FMN- and FAD-binding domains through an inferred dynamic cycle of open and closed conformations of the enzyme (PLoS Biol, 2011, e1001222). However, these studies were restricted to stopped-flow/FRET analysis of the reductive half-reaction, and were compromised by fluorescence quenching of the acceptor by the flavin cofactors. Here we have improved the design of the FRET system, by using dye pairs with near-IR fluorescence, and extended studies on human cytochrome P450 reductase to the oxidative half-reaction using a double-mixing ...
TY - JOUR. T1 - Induction of cytochrome P4501A isozymes by heterocyclic amines and other food-derived compounds.. AU - Kleman, M. I.. AU - Overvik, E.. AU - Poellinger, L.. AU - Gustafsson, Jan-Ake. PY - 1995/1/1. Y1 - 1995/1/1. N2 - The cytochrome P-4501A1 and P-4501A2 enzymes are involved in the metabolic activation of a number of environmental precarcinogens including the food-derived heterocyclic amines. These compounds also induce CYP1A activity in rats, a feature they have in common with several of the xenobiotics (most notably benzo[a]pyrene) which are metabolically activated by the cytochrome P-4501A isozymes. Using an in vitro DNA binding assay and an in vivo functional (transactivating) assay, we have found that the cytochrome P-4501A1 induction response produced by the heterocyclic amines is mediated by the intracellular dioxin receptor. In the absence of ligand, the receptor is inactive and does not bind DNA. In this report we demonstrate a correlation between activation of DNA ...
Almost one half of prospective drugs, including new chemical entities are not suitable for clinical use because of their metabolic unstability and for danger of drug interactions. This type of toxicity has been underlying several drug withdrawals in recent years and hence it is needed now to bring with any new compound proposed an information on its metabolism and on its interactions with major drug metabolizing enzyme systems namely with liver microsomal cytochromes P450 (CYP). Then, possibility of drug interactions with other drugs taken by the patient on the basis of drug metabolism may be evaluated to prevent significant losses in time, effort and money in drug development. The analysis of drug metabolism by individual CYPs, the possibility of drug interactions and of induction of individual CYP forms are performed with CYP in vitro systems with the respective substrates, inhibitors and inductors based on the recommendation of the U.S. Food and Drug Administration: ...
Meier U.T., Meyer U.A.. The metabolism of the anticonvulsant mephenytoin is subject to a genetic polymorphism. In 2-5% of Caucasians and 18-23% of Japanese subjects a specific cytochrome P-450 isozyme, P-450 meph, is functionally deficient or missing. We have accumulated evidence that autoimmune antibodies observed in sera of patients with tienilic acid induced hepatitis (anti-liver kidney microsome 2 or anti-LKM2 antibodies) specifically recognize the cytochrome P-450 involved in the mephenytoin hydroxylation polymorphism. This is demonstrated by immunoinhibition and immunoprecipitation of microsomal (S)-mephenytoin 4-hydroxylation activity and by the recognition by anti-LKM2 antibodies of a single protein band on immunoblots of human liver microsomes after sodium dodecyl sulfate-polyacrylamide gel electrophoresis or isoelectric focusing. The cytochrome P-450 recognized by anti-LKM2 antibodies was immunopurified from microsomes derived from livers of extensive (EM) or poor metabolizers (PM) of ...
en] Cytochrome P-450-dependent monooxygenases are able to oxidize a large variety of endogenous and exogenous substrates. This paper describes the in vitro interaction between benzopyrene and steroids at the level of two rat liver monooxygenases: steroid-16 alpha-hydroxylase and aryl hydrocarbon hydroxylase (AHH). The results obtained suggest the following conclusions: (1) Steroid-16 alpha-hydroxylase is partially supported by a specific cytochrome P-450 form which is not inhibited in vitro by exogenous substrates. Steroid-16 alpha-hydroxylase is completely independent from cytochrome P1-450 (or P-448), as it is insensitive, in vitro, to alpha-naphthoflavone; (2) AHH is supported by two cytochrome P-450 forms: a specific form which is inducible by methylcholanthrene and inhibited in vitro by alpha-naphthoflavone, but is insensitive to metyrapone and steroids; and another less specific form which is inhibited by metyrapone and steroids in vitro ...
A form of human hepatic microsomal cytochrome P-450 (P450hA7) with subunit Mr 50,400 has been purified from an epileptic who had been receiving long-term treatment with anticonvulsant drugs. P450hA7 metabolized the immunosuppressant drug cyclosporin A and the dihydropyridine calcium channel antagonist nifedipine, but did not metabolize a similar dihydropyridine drug, nicardipine, nor a series of alkoxyresorufin model substrates. The hepatic microsomal concentration of P450hA7 was higher in five individuals who had been receiving long-term anticonvulsant treatment than in any of 21 individuals who had not been similarly treated. The mean P450hA7 concentration in the treated individuals was 5-fold higher than the mean concentration in the untreated individuals. It is concluded that P450hA7 is a member of the cytochrome P450III family which is induced by anticonvulsant drugs in man. ...
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. A method based on thin layer chromatography was developed and used for measurement of microsomal skatole metabolism. Skatole metabolism by liver microsomes was inhibited by diallyl sulphide, a specific inhibitor of cytochrome P450IIE1 but not by inhibitors of other P450 isoforms. We have shown that the rate of skatole metabolism by liver microsomes was proportional to the microsomal P450IIE1 content. In LW pigs there was considerable variation in cytochrome P450IIE1 expression and P450IIE1 protein level and there was a significant negative correlation between backfat skatole level and hepatic microsomal cytochrome P450IIE1 content. Pigs exhibiting low P450IIE1 content in general also showed low levels of P450IIE1 mRNA. These results ...
Cytochrome P450s (CYPs) are a large, ubiquitous family of heme-containing monooxygenases that are responsible for the oxidative metabolism of a wide variety of drugs, environmental chemicals and endogenous compounds, such as steroids, prostaglandins and fatty acids[1].. Most cytochrome P450 systems are composed of a monooxygenase and one or two additional proteins, constituting an electron transfer chain. Genes encoding these components are either expressed individually or linked resulting in self sufficient CYPs. To some extent, the natural electron transport chain from NAD(P)H to the heme containing cytochrome P450 can be replaced by either homologues or different proteins with similar function e.g. flavodoxin and flavodoxin reductase to support catalytic activity[2]. Therefore, the activity of CYPs is not only determined by its abundance, but also by the abundance of the electron transport partners[3] and possibly by their molar ratio.. Eukaryotic CYPs are membrane associated and many of ...
TY - JOUR. T1 - Tyrosine Motions in Relation to the Ferric Spin Equilibrium of Cytochrome P-450cam. AU - Fisher, Mark T.. AU - Sligar, Stephen G.. PY - 1985/11/1. Y1 - 1985/11/1. N2 - Second derivative spectroscopy was used to determine the percentage of tyrosine residues that are exposed to solvent in cytochrome P-450cam isolated from Pseudomonas putida. The ratio between two peak to trough second derivative absorbance differences has been shown to be dependent on the polarity of the microenvironment surrounding tyrosine residues [Ragone, R., Colonana, G., Balestrieri, C, Servillo, L., & Irace, G. (1984) Biochemistry 23, 1871]. With a number of camphor analogues that independently vary the spin equilibrium of the ferric cytochrome P-450cam, experiments have demonstrated that the percentage of tyrosine residues exposed to solvent is linearly dependent on the percentage of ferric high-spin species present. This is not simply a function of the extent of substrate binding since in all cases the ...
TY - JOUR. T1 - Purification and characterization of a unique isozyme of cytochrome P-450 from liver microsomes of ethanol-treated rabbits. AU - Koop, D. R.. AU - Morgan, E. T.. AU - Tarr, G. E.. AU - Coon, M. J.. N1 - Copyright: Copyright 2004 Elsevier B.V., All rights reserved.. PY - 1982. Y1 - 1982. N2 - A new isozyme of cytochrome P-450 has been purified to electrophoretic homogeneity from hepatic microsomes of rabbits treated chronically with ethanol. Several criteria indicate that the ethanol-inducible cytochrome, which has a minimal molecular weight of 51,000 and is designated form 3a on the basis of its relative electrophoretic mobility, is distinct from the known isozymes of P-450. As judged spectrally, the new isozyme is high spin the oxidized state, as is form 4, but differs in that the spin state is unperturbed by nonionic detergents. The absolute spectrum of the ferrous carbonyl complex of form 3a is red shifted as compared to that of forms 2, 3b, 3c, 4, and 6 and exhibits a maximum ...
TY - JOUR. T1 - Regulation of the cerebral circulation by cytochrome P450 epoxygenase activity. AU - Peng, Xinqi. AU - Carhuapoma, Juan R.. AU - Bhardwaj, Anish. AU - Alkayed, Nabil J.. AU - Harder, David R.. AU - Traystman, Richard J.. AU - Koehler, Raymond C.. PY - 2002/7/1. Y1 - 2002/7/1. N2 - Cytochrome P450 epoxygenases metabolize arachidonic acid into epoxyeicosatrienoic acids (EETs), which can dilate cerebral vessels. In glial cell cultures, glutamate stimulates the release of EETs. Thus, an astrocyte-based epoxygenase pathway could form a link in the coupling of blood flow to neuronal activity. To test this hypothesis, neuronal activation was produced by mechanical displacement of the whiskers of anesthetized rats while monitoring red cell flux by laser-Doppler flowmetry over whisker barrel sensory cortex. N-methylsulfonyl-6-(2-propargyloxyphenol) hexanamide (MS-PPOH) or miconazole, two different types of P450 epoxygenase inhibitors, were superfused over the cortical surface in different ...
TY - JOUR. T1 - Possible association of NADPH-cytochrome P-450 reductase and cytochrome P-450 in reconstituted phospholipid vesicles. AU - Nisimoto, Yukio. AU - Kinosita, Kazuhiko. AU - Ikegami, Akira. AU - Kawai, Norio. AU - Ichihara, Ichiro. AU - Shibata, Yukio. PY - 1983. Y1 - 1983. N2 - A fluorescent probe, N-(1-anilinonaphth-4-yl)-maleimide (ANM), was specifically labeled to SH group(s) in the hydrophilic moiety of NADPH-cytochrome P-450 reductase at a ratio of 1 ± 0.1 ANM/mol of protein. The ANM-labeled reductase and P-450 were reconstituted in phosphatidylcholine-phosphatidylethanolamine-phosphatidylserine vesicles in which all of the enzymes were functionally active. The reconstitution of the mixed-function oxidase system was found to be strongly dependent on both the lipid to protein molar ratio and phospholipid composition. The interactions of ANM-labeled reductase with P-450 in proteoliposomes were investigated by perturbation of the fluorescence of ANM. Upon incorporation of P-450 ...
Cytokines are thought to cause the depression of cytochrome P-450 (CYP)-associated drug metabolism in humans during inflammation and infection. We have examined the role of five cytokines, i.e., interleukin-1 beta, interleukin-4, interleukin-6, tumor necrosis factor-alpha, and interferon-gamma, on the expression of CYP1A2, CYP2C, CYP2E1, CYP3A, and epoxide hydrolase in primary human hepatocyte cultures. Steady state P-450 and epoxide hydrolase mRNA levels, as well as ethoxyresorufin-O-deethylase and nifedipine oxidation activities, which are mainly supported by CYP1A1/1A2 and CYP3A, respectively, were measured. Interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha were found to be the most potent depressors of P-450 enzymes. After 3 days of treatment, both mRNA levels and enzyme activities were depressed, typically by at least 40%, whatever the cytokine and the enzyme considered. Interferon-gamma also suppressed CYP1A2 and CYP2E1 mRNA levels and ethoxyresorufin-O-deethylase activity ...
2,4,5-TCP 4-monooxygenase (TftD) and 2,4,6-TCP 4-monooxygenase (TcpA) have been discovered in the biodegradation of 2,4,5-trichlorophenol (2,4,5-TCP) and 2,4,6-trichlorophenol (2,4,6-TCP). TcpA and TftD belong to the reduced flavin adenine dinucleotide (FADH2)-dependent monooxygenases and both use 2,4,6-TCP as a substrate; however, the two enzymes produce different end products. TftD catalyzes a typical monooxygenase reaction, while TcpA catalyzes a typical monooxygenase reaction followed by a hydrolytic dechlorination. We have previously reported the 3D structure of TftD and confirmed the catalytic residue, His289. Here we have determined the crystal structure of TcpA and investigated the apparent differences in specificity and catalysis between these two closely related monooxygenases through structural comparison. Our computational docking results suggest that Ala293 in TcpA (Ile292 in TftD) is possibly responsible for the differences in substrate specificity between the two monooxygenases. We have
TY - JOUR. T1 - Cloning of rat cytochrome P450RAI (CYP26) cDNA and regulation of its gene expression by all-trans-retinoic acid in vivo. AU - Wang, Y.. AU - Zolfaghari, R.. AU - Catharine, Ross A.. PY - 2002/5/15. Y1 - 2002/5/15. N2 - A novel retinoic acid (RA)-inducible cytochrome P450 (P450 RAI or CYP26), previously cloned from human, zebra fish, and mouse, functions in the metabolism of all-trans-RA to polar metabolites including 4-hydroxy-RA and 4-oxo-RA. To further study CYP26 in the rat model, we first cloned rat CYP26 cDNA. The nucleotide sequence predicts a 497-amino-acid protein whose sequence is 95% identical to mouse and 91% homologous to human CYP26. Animal studies showed that CYP26 mRNA expression is very low (0.01 ± 0.008; P , 0.05) in vitamin-A-deficient rats compared to pair-fed vitamin-A-sufficient rats (defined as 1.0). In a kinetic study, vitamin-A-deficient rats were treated with ∼ 100 μg of all-trans-RA and liver was collected after 3-72 h for analysis of CYP26 mRNA by ...
Expression and monooxygenase activity of various cytochrome P450 (CYP) enzymes along with constitutive androstane (CAR) and the pregnane X (PXR) receptors were investigated in the brain of control and phenobarbital-treated rabbits (80 mg/kg for 4 days). RT-PCR analysis, using specific primers, demonstrated that in control rabbits mRNAs of CYP 2A10, 2B4/5 and 3A6 were expressed, though to a different extent, in the liver, as well as in brain cortex, midbrain, cerebellum, striatum, hippocampus and hypothalamus, whilst CYP2A11 and 4B1 were not expressed in the hypothalamus. CAR was expressed in liver and all the brain regions examined, whereas the PXR was expressed only in liver and cortex. Real time RT-PCR analysis demonstrated that in vivo treatment with phenobarbital, in contrast with what happened in liver, did not induce the expression of CYP 2B4/5 mRNA in cortex, midbrain and cerebellum. NADPH cytochrome c reductase and some other enzymatic activities markers of CYP 2A, 2B, 3A and 4B ...
Many studies using mammalian cellular and subcellular systems have demonstrated that polycyclic aromatic hydrocarbons, including benzo[a]pyrene (BaP), are metabolically activated by cytochrome P450s (CYPs). In order to evaluate the role of hepatic versus extra-hepatic metabolism of BaP and its pharmacokinetics, we used the hepatic cytochrome P450 reductase null (HRN) mouse model, in which cytochrome P450 oxidoreductase, the unique electron donor to CYPs, is deleted specifically in hepatocytes, resulting in the loss of essentially all hepatic CYP function. HRN and wild-type (WT) mice were treated intraperitoneally (i.p.) with 125 mg/kg body wt BaP daily for up to 5 days. Clearance of BaP from blood was analysed by high-performance liquid chromatography with fluorescence detection. DNA adduct levels were measured by 32P-post-labelling analysis with structural confirmation of the formation of 10-(deoxyguanosin-N2-yl)-7,8,9-trihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene by liquid chromatography-tandem ...
In vitro studies were conducted to investigate the potential of gabapentin to inhibit the major cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) that mediate drug and xenobiotic metabolism using isoform selective marker substrates and human liver microsomal preparations! Meldonium is a white crystalline powder, with a melting point of 87 °C (189 °F)! Although prescription anti-fungal drugs play an important role in the treatment of a yeast infection, tenormin price philippines prominently they still do not address the underlying cause of the overgrowth of Candida in the first place? Pharmacology and Physiology for Anesthesia: Foundations and Clinical Applications! What Is Meldonium, And Why Do Athletes Like Maria Sharapova Take It. For example, tab dutas t composition I could give a 10 patients sugar pills, and tell them that it may cause some gastrointestinal discomfort? Psilocybin is the major hallucinognic constituent of the mushrooms and psilocin is ...
Both the CL of docetaxel and CYP3A4 activity, as measured by the ERMBT, had marked interpatient variation in this study. All patients were required to have good hepatic function as described previously, and with the exception of dexamethasone, no patient received known potent inhibitors or inducers of CYP3A4. Thus, it appears that the variation seen could reflect genetic differences in the metabolism of docetaxel.. The most significant independent variable examined to predict docetaxel CL in this study was hepatic CYP3A4 activity as measured by ERMBT. Previously, the best predictors of docetaxel pharmacokinetics that had been identified were abnormal liver chemistries and serum AAG level. Albumin was also a significant predictor of CL, but its effect was of low magnitude compared with that of AAG (9) . In this study, AAG and the ERMBT results do not appear to be correlated, and the ERMBT is a superior predictor of CL. In fact, the ERMBT and albumin are the strongest predictors of CL, and ...
Title:Murburn Precepts for Cytochrome P450 Mediated Drug/Xenobiotic Metabolism and Homeostasis. VOLUME: 22 ISSUE: 4. Author(s):Abhinav Parashar* and Kelath M. Manoj*. Affiliation:Satyamjayatu: The Science & Ethics Foundation, Snehatheeram, Kulappully, Shoranur-2 (PO), Kerala-679122, Satyamjayatu: The Science & Ethics Foundation, Snehatheeram, Kulappully, Shoranur-2 (PO), Kerala-679122. Keywords:Cytochrome P450 (CYP), murburn concept, drug/xenobiotic metabolism, pharmacokinetics, diffusible reactive oxygen species (DROS), CYP3A4.. Abstract:Aims: We aim to demonstrate why deeming diffusible reactive oxygen species (DROS) as toxic wastes do not afford a comprehensive understanding of cytochrome P450 mediated microsomal xenobiotic metabolism (mXM). Background: Current pharmacokinetic investigations consider reactive oxygen species formed in microsomal reactions as toxic waste products, whereas our works (Manoj et al., 2016) showed that DROS are the reaction mainstay in cytochrome P450 mediated ...
Cytochrome P-450 (P-450) 2A6 was purified by chromatography of human liver microsomes. The final preparation was electrophoretically homogeneous and contained 16 nmol of P-450/mg of protein. The amino-terminal amino acid sequence of the protein (first 13 residues) matched that of the reported cDNA exactly. The UV-visible spectrum indicated that the isolated hemoprotein was in the low-spin form. The protein was recognized by rabbit antibodies raised against rat P-450 2A1, and a rabbit antiserum against the P-450 2A6 preparation was also prepared. With these antibodies, it was estimated that P-450 2A6 accounted for a maximum of 1% of the total P-450 present in the human liver microsomes; the level varied greater than 100-fold among the 20 samples examined. Purified P-450 2A6 catalyzed coumarin 7-hydroxylation and 7-ethoxycoumarin O-deethylation at rates similar to those measured in the human liver sample used to prepare P-450 2A6, and these two microsomal activities were strongly inhibited by the ...
A new cytochrome P-450 isozyme (Mr = 52,000) was purified to apparent electrophoretic homogeneity from hepatic microsomes of mice treated with acetone and its biochemical, spectral, and immunological properties characterized. Several criteria indicated that the purified cytochrome was distinct from the known mouse P-450 isozymes. The absolute spectrum of its oxidized form indicated that it was in the high spin state. In a reconstituted system, it showed low catalytic activities towards 7-ethoxycoumarin, aminopyrine, and coumarin, whereas it catalyzed the oxidation of aniline, acetone, dimethylnitrosamine with high turnover number. The mouse enzyme was immunoreactive with polyclonal antibodies against rat P-450IIE1 and exhibited an NH2-terminal aminoacid sequence with a high homology to that of rat-P-450IIE1. Based upon the above catalytic, spectral, immunological and structural properties, the purified mouse P-450 appears to be the ortholog of previously described P-450IIE1(s) of other species ...
TY - JOUR. T1 - New combined model for the prediction of regioselectivity in cytochrome P450/3A4 mediated metabolism. AU - Oh, Won Seok. AU - Kim, Doo Nam. AU - Jung, Jihoon. AU - Cho, Kwang Hwi. AU - No, Kyoung Tai. PY - 2008/3. Y1 - 2008/3. N2 - Cytochrome P450 3A4 metabolizes nearly 50% of the drugs currently in clinical use with a broad range of substrate specificity. Early prediction of metabolites of xenobiotic compounds is crucial for cost efficient drug discovery and development. We developed a new combined model, MLite, for the prediction of regioselectivity in the cytochrome P450 3A4 mediated metabolism. In the model, the ensemble catalyticphorebased docking method was implemented for the accessibility prediction, and the activation energy estimation method of Korzekwa et al. was used for the reactivity prediction. Four major metabolic reactions, aliphatic hydroxylation, N-dealkylation, O-dealkylation, and aromatic hydroxylation reaction, were included and the reaction data, metabolite ...
HETEROLOGE GENEXPRESSION, EXPRESSION VON FREMDGENEN (GENETIK); SACCHAROMYCES (MYKOLOGIE); CYTOCHROM-P-450-ABHÄNGIGE MONOOXYGENASEN (ENZYME); HETEROLOGOUS GENE EXPRESSION + EXPRESSION OF FOREIGN GENES (GENETICS); SACCHAROMYCES (MYCOLOGY); CYTOCHROME P-450 DEPENDENT MONOOXYGENASES (ENZYMES ...
Protein target information for Multifunctional 2-oxoglutarate metabolism enzyme (Mycobacterium tuberculosis CDC1551). Find diseases associated with this biological target and compounds tested against it in bioassay experiments.
The body removes xenobiotics by xenobiotic metabolism. Hepatic CYP2B6 enzymes are responsible for the metabolism of Xenobiotics by first activating them. An example of a enzyme involved in xenobiotic metabolism is hepatic microsomal cytochrome P450 Myristicin from parsley leaf oil [5-allyl-1-methoxy-2,3-(methylenedioxy) benzene, known to produce significant psychopharmacological responses as well as insecticidal activity.] a chemopreventive agent detoxified by the mu class GST might occur through an Ah [the Hepa-1 cytosolic aryl hydrocarbon (Ah)] receptor-independent pathway. Indicated that the saturation of the isolated double bond a mechanism for its inhibition of B[a]P [benzo[a]pyrene] or other carcinogens that may be detoxified in the same manner. Involves increases in mRNA levels except in the case of P4502E1. These metabolites were excreted [confirmed in urine] as conjugated forms as well, clones are sequence-verified shRNA lentiviral plasmids particles at 106 TU/ml the parental vector ...
Objectives : The mechanisms for korean traditional medicine-drug interaction has not been well reviewed in spite that the chance for co-administration with western drugs or diet supplements has been increased. Especially, it is well known that various cytochrome P450s play a major role in drug-drug interaction. Of course, Korean traditional medicines is not excluded in a view of metabolism or biotransformation by cytochrome P450. This article was focused on reviewing the possible roles of cytochrome P450 in Korean traditional medicine-drug interaction, Also, the directions for further studies were suggested in terms of Korean traditional medicine-drug interaction. Methods : New studies for korean traditional medicine-drug interaction were reviewed and summarized in terms of cytochrome P450 activities by various Korean traditional medicines and western drugs. Results and Conclusions : Even if a few studies related to Korean traditional medicine-drug interactions was carried out, almost no studies for
1648 Estrogen metabolism plays an important role in breast cancer causation. Several cytochrome P450 enzymes are involved in the Phase I metabolism of 17β-estradiol. Of these, the primary extra-hepatic enzymes are CYP1A1 and CYP1B1. Polymorphisms associated with both genes are known to affect breast cancer risk. CYP1B1 predominantly converts estradiol to a 4-hydroxy metabolite. However, recent data suggest that CYP1A1 can also convert estradiol to 4-hydroxy metabolite, in addition to 2-hydroxylation (Cribb AE et al., 2006). We postulate that CYP1A1 may play an important role in estrogen-induced rat mammary tumorigenesis. Female ACI rats (10-week old) were treated with 3-cm silastic implants containing 27 mg 17ß-estradiol and were euthanized at 6, 12, 18 and 24 weeks after treatment. This treatment is known to produce mammary tumors in almost 100% of the animals at 24 weeks. The mRNA expression of both CYP1A1 and CYP1B1 was analyzed using quantitative real-time PCR in the mammary tissue of ...
TY - JOUR. T1 - The prediction of drug metabolism using scaffold-mediated enhancement of the induced cytochrome P450 activities in fibroblasts by hepatic transcriptional regulators. AU - Chiang, Tsai Shin. AU - Yang, Kai Chiang. AU - Zheng, Shu Kai. AU - Chiou, Ling Ling. AU - Hsu, Wen Ming. AU - Lin, Feng Huei. AU - Huang, Guan Tarn. AU - Lee, Hsuan Shu. PY - 2012/7. Y1 - 2012/7. N2 - A reliable, reproducible, and convenient in vitro platform for drug metabolism determination and toxicity prediction is of tremendous value but still lacking. In the present study, a collection of 24 hepatic transcription factors and nuclear receptors in different combinations were surveyed, and 10 among them were finally selected to induce the expression and enzyme activities of cytochrome P450 (CYP) 3A4, 1B1, and 2C9 in human dermal fibroblasts (HDFs). The expression and activities of these CYPs in the induced HDFs were higher than those in commonly used hepatoma cell lines. High CYP expression and activities ...
Background. All-trans retinoic acid (atRA) plays an essential role in the regulation of gene expression, cell growth and differentiation and is also important for normal cardiovascular development but may in turn be involved in cardiovascular diseases, i.e. atherosclerosis and restenosis. The cellular atRA levels are under strict control involving several cytochromes P450 isoforms (CYPs). CYP26 may be the most important regulator of atRA catabolism in vascular cells. The present study describes the molecular cloning, characterization and function of atRA-induced expression of a spliced variant of the CYP26B1 gene.. Methodology/Principal Findings. The coding region of the spliced CYP26B1 lacking exon 2 was amplified from cDNA synthesized from atRA-treated human aortic smooth muscle cells and sequenced. Both the spliced variant and full length CYP26B1 was found to be expressed in cultured human endothelial and smooth muscle cells, and in normal and atherosclerotic vessel. atRA induced both ...
The biosynthesis of steroid hormones is an integral component of insect growth, development and reproduction. Although there is an abundance of biochemical data implicating both microsomal and mitochondrial cytochrome P450s in steroid metabolism, molecular genetic information on mitochondrial P450s is almost entirely limited to vertebrate sequences. In the current study, a degenerate polymerase chain reaction (PCR) primer was targeted to the highly conserved region of P450 genes that encodes the heme-binding decapeptide. Using a 5 rapid amplification of cDNA ends (RACE) approach, seven novel cytochrome P450 genes were isolated from Drosophila acanthoptera, including one sequence (CYP12B1) with high regional homology to vertebrate mitochondrial P450s. Sequence analysis of the conceptual translation of the full length gene, obtained by 5RACE, revealed an amphipathic NH2-terminus rich in basic and hydrophilic amino acids, a characteristic feature of mitochondrial P450s that distinguishes them ...
BioAssay record AID 769674 submitted by ChEMBL: Drug metabolism in human liver microsomes assessed as CYP3A4-mediated metabolite formation in presence of ketaconozole.
The proposed research program addresses important questions concerning the mechanism, structure, specificity, and biological roles of cytochrome P450 enzymes, enzymes that play critical roles in sterol and lipid biogenesis, drug and xenobiotic elimination, drug interactions, carcinogenicity and toxicity, and as potential tools in biotechnology. One focus of the research program is on bacterial P450 enzymes as structurally defined systems in which to elucidate the general features of cytochrome P450 mechanism and specificity relevant to the mammalian enzymes. The second focus is on the mammalian CYP4 family of fatty acid m-hydroxylases that oxidize arachidonic acid to eicosanoids involved in the control of vascular pressure. The two facets of the program are linked by an underlying concern with structure and mechanism. We specifically propose the following: (a) To further define the mechanism of cytoctuome P450 enzymes, with emphasis on the proposed role of the radical rebound mechanism in ...
The liver cytochrome P-450 oxidase system stimulating drugs such as phenytoin, phenobarbital and so on if administered with cyclophosphamide, it can increase the rate of metabolism of cyclophosphamide to its cytotoxic metabolites. In this setting, the physician should be alert for possible desirable or undesirable effects. Sometimes, the dose may need to be adjusted or liver cytochrome P-450 oxidase system stimulating drugs should be avoided.. ...
Microsomes are an ideal medium to investigate cytochrome P450 (CYP450) enzyme-mediated drug metabolism. However, before microsomes are prepared, tissues can be stored for a long time. Studies about...