Direct inhibitions of the activities of steroidogenic cytochrome P-450 mono-oxygenase systems by anticonvulsants.
The effects of anticonvulsants on the activities of cytochromes P-450(17alpha,lyase) (CYP17), P-450arom (CYP19), P-450C21 (CYP21), P-450SCC (CYP11A1), and P-450(11beta) (CYP11B1) mono-oxygenase systems were studied using rat testicular microsomes, human placental microsomes, bovine adrenocortical microsomes, bovine adrenocortical mitochondria and purified cytochrome P-450(11beta). Phenytoin, clonazepam and carbamazepine inhibited the steroidogenesis catalysed by these cytochrome P-450 mono-oxygenase systems and the Ki values for each anticonvulsant were determined. Neither hydantoin nor sodium valproate inhibited the activities of steroidogenic cytochromes P-450. When the activities of cytochromes P-450arom and P-450C21 were measured in the presence of anticonvulsants, the Ki values (0.15 mM) for phenytoin were close to the plasma concentration of phenytoin under therapeutic conditions. Phenytoin, clonazepam and carbamazepine directly inhibited the monooxygenase activities of cytochromes P-450, because they did not affect the activities of NADPH-cytochrome P-450 reductase, NADPH-adrenoferredoxin reductase and adrenoferredoxin.
Ohnishi
T
T
Department of Biochemistry, Kagawa Medical School, Kita-gun, Japan.
Ichikawa
Y
Y
D000325:Adrenodoxin / Q000187:drug effects / Q000378:metabolism; D000735:Androstenedione / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001141:Aromatase / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D002784:Cholesterol / Q000378:metabolism; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000187:drug effects / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism*; D003900:Desoxycorticosterone / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D004970:Estrone / Q000378:metabolism; D005260:Female; D005287:Ferredoxin-NADP Reductase / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000187:drug effects / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase; D010920:Placenta / Q000187:drug effects / Q000201:enzymology; D011247:Pregnancy; D011284:Pregnenolone / Q000378:metabolism; D011374:Progesterone / Q000378:metabolism; D051381:Rats; D013252:Steroid 11-beta-Hydroxylase / Q000187:drug effects / Q000378:metabolism; D013254:Steroid 17-alpha-Hydroxylase / Q000187:drug effects / Q000378:metabolism; D013255:Steroid 21-Hydroxylase; D013256:Steroids / Q000378:metabolism*; D013737:Testis / Q000187:drug effects / Q000378:metabolism
D000927:Anticonvulsants; D065607:Cytochrome P-450 Enzyme Inhibitors; D004967:Estrogens; D013256:Steroids; D000325:Adrenodoxin; D004970:Estrone; D000735:Androstenedione; D003900:Desoxycorticosterone; D011374:Progesterone; D011284:Pregnenolone; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D001141:Aromatase; D013255:Steroid 21-Hydroxylase; D013254:Steroid 17-alpha-Hydroxylase; C022445:progesterone 17-alpha-hydroxylase; D013252:Steroid 11-beta-Hydroxylase; D002786:Cholesterol Side-Chain Cleavage Enzyme; D005287:Ferredoxin-NADP Reductase; D009247:NADH, NADPH Oxidoreductases; D009251:NADPH-Ferrihemoprotein Reductase