In vitro inhibition studies of two isozymes of human liver cytochrome P-450. Mephenytoin p-hydroxylase and sparteine monooxygenase.
Human liver preparations were used to screen various drugs for their capability of binding to mephenytoin p-hydroxylase and sparteine monooxygenase, two cytochrome P-450-catalyzed activities that are independently heritable. For this screening, any indication of competitive inhibition by the drug was interpreted as an indication of binding. Among 64 drugs and alkaloids tested, 24 compounds caused inhibition of mephenytoin p-hydroxylation but the inhibition was weak in most cases; by contrast, 40 of the 64 compounds inhibited sparteine oxidation, the inhibition being potent in many cases. The only fairly strong inhibitors of mephenytoin p-hydroxylation were the alkaloid papaverine and the monoamine oxidase inhibitors tranylcypromine and nialamide. The results of these inhibition studies confirm the independence of the two monogenic defects observed in different populations. Metabolism is possibly altered in poor metabolizers of mephenytoin with fewer drugs than in poor metabolizers of sparteine.
Inaba
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Jurima
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Mahon
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Kalow
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D000470:Alkaloids / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases; D001667:Binding, Competitive; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008099:Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding
D000470:Alkaloids; D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6