Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: KEGG:D06103 (Theophylline)
 2,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The metabolism of the progestogen gestodene has been studied in human liver cytosol and microsomal incubations. Extraction with diethyl ether was followed by radiometric HPLC analysis. Metabolites were identified by co-chromatography with authentic standards and mass spectrometry (electron impact and chemical ionization). All the cytosolic incubations (n = 4 livers) produced dihydrogestodene as the major metabolite, with lesser amounts of a tetrahydro derivative. It was not possible to separate the 5 alpha- and 5 beta-isomers of dihydrogestodene on the chromatographic system used. Values of Km and V(max) for the delta 4 reductase were determined. Androstenedione (Ki = 2.85 +/- 1.5 microM; n = 4) and cortisol (ki = 24.1 +/- 8.9 microM; n = 4) both inhibited the delta 4-reductase. In contrast desogestrel showed virtually no inhibition at concentrations up to 200 microM. The major microsomal metabolite of gestodene was a hydroxylated derivative although mass spectral analysis was unable to determine the position of insertion of the hydroxyl moiety. The hydroxylation of gestodene (1 microM) was markedly inhibited by ketoconazole (IC50 < 0.1 microM), and also by cyclosporin. This suggests that the cytochrome P450 isozyme CYP3A4 is important in gestodene metabolism. Theophylline and tolbutamide (substrates of CYPIA and CYP2C, respectively) did not affect gestodene metabolism at concentrations up to 100 microM. In conclusion, the major biotransformation of gestodene (A-ring reduction) occurs in the cytosolic fraction of human liver. Microsomal hydroxylation appears to be catalysed by CYP3A4.
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PMID:Metabolism of gestodene in human liver cytosol and microsomes in vitro. 866 72

We examined the inhibitory effect of moricizine (MOR) on hepatic cytochrome P-450 (CYP) in mice. Spectrophotometric analysis revealed that MOR had a relatively high affinity for CYP molecules. MOR most potently inhibited the CYP1A1-dependent ethoxyresorufin O-deethylation and the CYP1A2-dependent methoxyresorufin O-demethylation, among the metabolic reactions mediated by CYP1A, CYP2A, CYP2B, CYP2C, CYP2D, CYP2E, and CYP3A subfamilies expressed in untreated and CYP-inducer-treated hepatic microsomes. The inhibition constants (K(i)) for ethoxyresorufin and methoxyresorufin O-dealkylations were 0.43 and 0.98 micromol/l, respectively. These K(i) values were one to three orders of magnitude lower than those of cimetidine (CIM) and mexiletine (MEX) that have been accepted as the clinical inhibitors of CYP1A2 and were below the therapeutic serum concentration of MOR. Theophylline 3-demethylation and 8-hydroxylation in untreated hepatic microsomes, clinical probes for CYP1A2 activities, were subjected to marked and competitive inhibition by MOR with K(i) values similar to that of methoxyresorufin O-demethylation, and the inhibitory potency of MOR was much higher than those of CIM and MEX. In addition, the zoxazolamine paralysis time, an in vivo measure of the hepatic CYP1A2 capacity, was markedly prolonged by pretreatment of mice with MOR rather than CIM and MEX, while the prolonging effect of MOR on the pentobarbital sleeping time, an indicator of the metabolic function of phenobarbital-inducible CYP species, was not so pronounced as compared with the zoxazolamine paralysis time. These results indicate that MOR acts as a potent and preferential inhibitor of hepatic CYP1A enzymes in vitro and in vivo.
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PMID:Moricizine, an antiarrhythmic agent, as a potent inhibitor of hepatic microsomal CYP1A. 1239 41