Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.14.13.97 (CYP3A4)
 6,365 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ergot alkaloid CQA 206-291 (CQA) was converted by human liver microsomes (n = 16) almost exclusively to the N-deethylated metabolite (I), as identified by the on-line coupling of liquid chromatography and mass spectroscopy. Metabolite I formation exhibited monophasic and linear enzyme kinetics (2.9-300 microM), and a 5.6-fold interindividual variability (7.2-40.2 nmol/mg/hr). Chemical inhibition experiments revealed that imidazole antimycotic agents (ketoconazole, miconazole, and clotrimazole) were potent inhibitors of this N-deethylation. Polymorphically metabolized substrates (sparteine and phenytoin), well-established cytochrome P-450 probe substrates (antipyrine and tolbutamide), and steroid hormones (estradiol and testosterone) were noninhibitory, indicating that their metabolism is catalyzed by forms of cytochrome P-450 that do not catalyze this route of CQA biotransformation. The ergot alkaloids--dihydroergotamine, bromocriptine, and SDZ 208-911--were competitive inhibitors of metabolite I formation, suggesting that these compounds are metabolized by similar enzymes. Cyclosporine A was a potent competitive inhibitor of CQA metabolism, providing initial evidence that formation of metabolite I was catalyzed by proteins of the CYP3 gene family. This was substantiated by the finding that CQA metabolism was completely inhibited by a polyclonal antibody directed against a pregnenolone 16 alpha-carbonitrile-inducible cytochrome P-450 of rat liver. The rate of CQA metabolism correlated significantly to the level of CYP3A4 expression, the rate of cyclosporine A metabolism to each of the primary metabolites (M-1, M-17, and M-21), and the rate of midazolam 4-hydroxylation. COS 1 cells transfected with human CYP3A4 and CYP3A5 provided direct evidence that these enzymes catalyze the metabolism of CQA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of the cytochrome P-450 gene family responsible for the N-dealkylation of the ergot alkaloid CQA 206-291 in humans. 134 97

We have used a full length cDNA clone (2.2 kb) for the human cytochrome P-450 nifedipine oxidase (CYP3A4) enzyme as a probe to determine its chromosome localization by fluorescence in situ hybridization. CYP3A4 was mapped on R-banded human prometaphase chromosomes, and the precise localization of CYP3A4 on chromosome 7 was further confirmed by a delineation of G-banded pattern on the same prometaphase chromosomes through a combination of UV-filter. We assigned CYP3A4 to chromosome 7 at q22.1.
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PMID:Assignment of the human cytochrome P-450 nifedipine oxidase gene (CYP3A4) to chromosome 7 at band q22.1 by fluorescence in situ hybridization. 139 68

A human B-lymphoblastoid cell line, designated MCL-5, constitutively expressing human cytochrome P-450 CYP1A1 and also expressing five transfected human cDNAs encoding drug-metabolizing enzymes, has been developed. cDNAs encoding CYP1A2, CYP2A6, and microsomal epoxide hydrolase (mEH) were introduced by using a vector conferring hygromycin B resistance, and cDNAs encoding CYP2E1 and CYP3A4 were introduced by using a vector conferring resistance to 1-histidinol. MCL-5 cells stably expressed all five cDNAs and the native CYP1A1 as determined by measurement of form-specific enzyme activity levels. The mutagenicity of seven model procarcinogens to MCL-5 cells was examined at the hypoxanthine guanine phosphoribosyltransferase (hprt) and thymidine kinase (tk) loci. Exposure to benzo[a]pyrene (BP), 3-methylcholanthrene (3MC), N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), aflatoxin B1, (AFB1), 2-(acetylamino)fluorene (AAF), or benzidine (BZD) induced a statistically significant increase in mutant frequency. Linear interpolation of the concentration of procarcinogen necessary to produce a doubling of the mutant fraction at the hprt locus in MCL-5 cells and the parent AHH-1 cell line revealed that, for each of the chemicals examined, except BZD, MCL-5 cells were significantly more sensitive than the parent AHH-1 cells. The increase in sensitivity to mutagenicity ranged from 3-fold for AAF to greater than 40,000-fold for NDMA. MCL-5 cells have great potential as a screening system for the analysis of human procarcinogen/promutagen activation.
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PMID:A metabolically competent human cell line expressing five cDNAs encoding procarcinogen-activating enzymes: application to mutagenicity testing. 179 7

Macrolide antibiotics can interact adversely with commonly used drugs, usually by altering metabolism due to complex formation and inhibition of cytochrome P-450 IIIA4 (CYP3A4) in the liver and enterocytes. In addition, pharmacokinetic drug interactions with macrolides can result from their antibiotic effect on microorganisms of the enteric flora, and through enhanced gastric emptying due to a motilin-like effect. Macrolides may be classified into 3 different groups according to their affinity for CYP3A4, and thus their propensity to cause pharmacokinetic drug interactions. Troleandomycin, erythromycin and its prodrugs decrease drug metabolism and may produce drug interactions (group 1). Others, including clarithromycin, flurithromycin, midecamycin, midecamycin acetate (miocamycin; ponsinomycin), josamycin and roxithromycin (group 2) rarely cause interactions. Azithromycin, dirithromycin, rikamycin and spiramycin (group 3) do not inactivate CYP3A4 and do not engender these adverse effects. Drug interactions with carbamazepine, cyclosporin, terfenadine, astemizole and theophylline represent the most frequently encountered interactions with macrolide antibiotics. If the combination of a macrolide and one of these compounds cannot be avoided, serum concentrations of concurrently administered drugs should be monitored and patients observed for signs of toxicity. Rare interactions and those of dubious clinical importance are those with alfentanil and sufentanil, antacids and cimetidine, oral anticoagulants, bromocriptine, clozapine, oral contraceptive steroids, digoxin, disopyramide, ergot alkaloids, felodipine, glibenclamide (glyburide), levodopa/carbidopa, lovastatin, methylprednisolone, phenazone (antipyrine), phenytoin, rifabutin and rifampicin (rifampin), triazolam and midazolam, valproic acid (sodium valproate) and zidovudine.
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PMID:Macrolide antibacterials. Drug interactions of clinical significance. 757 62

1. Theophylline metabolism was studied using seven human cytochrome P-450 isoforms (CYPs), namely CYP1A1, 1A2, 2A6, 2B6, 2D6, 2E1 and 3A4, and microsomal epoxide hydroxylase (EH), expressed in human B-lymphoblastoid cell lines. 2. At a high theophylline concentration of 10 mM four CYPs (1A1, 1A2, 2D6, 2E1) catalyzed the metabolism of theophylline. 3. Theophylline had the highest affinity (apparent Km range 0.2-1.0 mM) for the CYP1A subfamily and the kinetics of metabolic formation mediated by CYP1A2 indicated substrate-inhibition (Ki range 9-16 mM). 4. CYP1A2 catalyzed the demethylation of theophylline as well as its hydroxylation, and was associated with the highest intrinsic clearance (1995 l h-1 per mol CYP) to 1,3-dimethyluric acid (DMU). Therefore, this isoform can be considered to be the most important enzyme involved in theophylline metabolism in vitro. 5. CYP2E1 was responsible for a relatively high intrinsic clearance by 8-hydroxylation (289 l h-1 per mol CYP). The apparent Km value of this reaction was about 15 mM, suggesting that CYP2E1 may be the low-affinity high-capacity isoform involved in theophylline metabolism. 6. The affinity of theophylline for CYP1A1 was comparable with that of its homologue 1A2. When induced, the participation of CYP1A1 in theophylline metabolism may be important. 7. CYP2D6 played only a minor role and CYP3A4 was not active in the in vitro metabolism of theophylline. 8. Our findings confirm the major role of CYP1A2 in theophylline metabolism and explain why in vivo the elimination kinetics of theophylline are non-linear and in vitro theophylline metabolism by human liver microsomes does not obey monophasic kinetics. 9. The data suggest also that not only tobacco smoking but also chronic alcohol intake may influence theophylline elimination in man as ethanol induces CYP2E1.
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PMID:Metabolism of theophylline by cDNA-expressed human cytochromes P-450. 761 75

Drug metabolism input to the discovery process has been to date largely on an empirical case by case basis. Considerable advances have been made, such that basic rules can be applied to the behaviour of a compound in man based on physico-chemistry and structure. This is particularly true in the area of the cytochrome P-450 enzymes, the principal enzymes involved in the primary clearance of drugs. The major human forms, CYP2D6, CYP2C9 and CYP3A4 all have distinct substrate preferences which are being catalogued and rationalised. Such understandings will not only impact on existing drugs. Since the enzymes and systems will remain the same, these understandings can be applied to the design of molecules for the targets of the future, whilst the structure activity relationships of those targets are being researched and revealed.
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PMID:Design of drugs through a consideration of drug metabolism and pharmacokinetics. 786 61

Metabolic N-dealkylation is a commonly observed biotransformation with tertiary and secondary amine drugs and related N-alkylated amides, but surprisingly little is known about the cytochrome P-450 isozymes involved in these dealkylation reactions. In this review, evidence is provided that supports the involvement of various P-450 isozymes, but especially CYP3A4 and other isozymes of the CYP3A subfamily. Although CYP2D6 is generally not considered to be capable of catalyzing the N-dealkylation of basic drugs, some examples of the involvement of this important isozyme in N-dealkylation reactions are identified. Procedures used to identify individual P-450 isozymes involved in N-dealkylation reactions are discussed.
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PMID:Involvement of CYP2D6, CYP3A4, and other cytochrome P-450 isozymes in N-dealkylation reactions. 794 73

Tropisetron and ondansetron, which are potent and selective 5-hydroxytryptamine (5-HT3) receptor antagonists, were both metabolized by human liver microsomes to several metabolites. These metabolites include the major metabolites found in humans, which are the 5-, 6-, and 7-hydroxy tropisetron and the 7- and 8-hydroxy ondansetron. The cytochrome P-450 (CYP) 2D6 inhibitor quinidine (1 microM) reduced the hydroxylation of tropisetron (67%) and ondansetron (18%). Confirmation of CYP2D6 involvement in the hydroxylation of tropisetron and ondansetron was obtained by the formation of these metabolites in recombinant V79 cells expressing human CYP2D6. The CYP3A substrate/inhibitor, cyclosporine A (CsA) had little effect on tropisetron hydroxylation (< 10%), whereas CsA and triacetyloleandomycin reduced ondansetron 7- and 8-hydroxylation up to 27%. Substrates for CYP1A (phenacetin and acetanilide), CYP2C (mephenytoin), and CYP2E (chlorzoxazone) had negligible inhibitory effects on the hydroxylation of either tropisetron or ondansetron. For the CYP2D6-dependent O-demethylation of dextromethorphan, tropisetron and ondansetron were competitive inhibitors with Ki values of 14 and 29 microM, respectively. The CYP3A specific metabolism of CsA was also competitively inhibited by tropisetron (Ki = 2.1 mM) and ondansetron (Ki = 31 microM). Other metabolites, which are only minor in vivo were also inhibited by CsA, 47-60% for tropisetron metabolism and 43% for ondansetron metabolism. To summarize, this study has identified the involvement of CYP2D6 in the formation of the hydroxylated metabolites of tropisetron and ondansetron and in addition of CYP3A in ondansetron hydroxylation. Because these are the major pathways in vivo, coadministration of drugs competing for CYP2D6 and possibly CYP3A4 could influence the human kinetics of tropisetron and ondansetron.
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PMID:The polymorphic cytochrome P-4502D6 is involved in the metabolism of both 5-hydroxytryptamine antagonists, tropisetron and ondansetron. 801 82

We describe the case of a depressive patient who was a rapid metabolizer of CYP2D6 substrates and a heavy smoker, and who did not respond to several courses of treatment with antidepressants, as a result of unusually low drug-plasma levels. During hospitalization, he did not improve after treatment with clomipramine (150-225 mg/day during three weeks), but showed a response within four days after addition of fluvoxamine (100 mg/day). Plasma levels of clomipramine and desmethylclomipramine changed from 58 ng/ml and 87 ng/ml to 223 ng/ml and 49 ng/ml respectively one week after addition of fluvoxamine. Present knowledge of the role of cytochrome P-450 isozymes, such as CYP1A2, CYP2C19, CYP2D6, and CYP3A4, in the metabolism of psychotropic drugs as well as therapeutic drug-plasma level monitoring may thus help to determine individual treatment.
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PMID:Pharmacokinetic fluvoxamine-clomipramine interaction with favorable therapeutic consequences in therapy-resistant depressive patient. 873 15

Studies were carried out to test the hypothesis that inflammatory liver disease increases the expression of specific cytochrome P-450 isoenzymes involved in aflatoxin B1 (AFB) activation. The immunohistochemical expression and localization of various human cytochrome P-450 isoforms, including CYP2A6, CYP1A2, CYP3A4, and CYP2B1, were examined in normal human liver and liver with hepatitis and cirrhosis. The constitutive expression of CYP3A4 in normal liver showed a characteristic pattern of distribution in centrilobular hepatocytes, whereas CYP1A2, CYP2A6, and CYP2B1 were expressed uniformly throughout the liver acinus. In sections of liver infected with hepatitis B virus (HBV) or hepatitis C virus (HCV), the expression of CYP2A6 was markedly increased in hepatocytes immediately adjacent to areas of fibrosis and inflammation. CYP3A4 and CYP2B1 were induced to a lesser degree, and expression of CYP1A2 was unaffected. In HBV-infected liver, double immunostaining revealed that overexpression of CYP2A6 occurred in hepatocytes expressing the HBV core antigen. In HCV-infected liver, CYP2A6, CYP3A4, and CYP2B1 were overexpressed in hepatocytes with hemosiderin pigmentation. These results suggest that alterations in phenotypic expression of specific P-450 isoenzymes in hepatocytes associated with hepatic inflammation and cirrhosis might increase susceptibility to AFB genotoxicity.
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PMID:Overexpression of cytochrome P-450 isoforms involved in aflatoxin B1 bioactivation in human liver with cirrhosis and hepatitis. 886 87


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