Progesterone metabolism in hepatic microsomes. Effect of the cytochrome P-450 inhibitor, ketoconazole, and the NADPH 5 alpha-reductase inhibitor, 4-MA, upon the metabolic profile in human, monkey, dog, and rat.
Progesterone was incubated in the presence of NADPH with hepatic microsomes isolated from male and female human, monkey, dog, and rat and the effect of 17 beta-NN-diethylcarbamoyl-4-methyl-4-aza-5 alpha- androstan-3-one (4-MA), an NADPH 5 alpha-reductase inhibitor, and ketoconazole, a cytochrome P-450 inhibitor, upon oxidative metabolism was evaluated. 4-MA caused an increase in detectable oxidative products only with microsomes isolated from rat. An increase in 2 alpha- and 16 alpha-hydroxylation was observed in male rat, and an increase in the formation rate of nine products was observed in female rat. delta 6-Progesterone, 6 beta-, 15 alpha-, 16 alpha-, and 21-hydroxyprogesterone (6 beta-, 15 alpha-, 16 alpha-, and 21-OHP) were common products in both sexes of all species studied. Differences were observed in the formation rate of 2 alpha-, 2 beta-, 6 alpha-, 7 alpha-, and 17 alpha-OHPs. At the 2-carbon, microsomes isolated from both sexes of primates hydroxylated progesterone exclusively at the 2 beta-position. Microsomes from both dog sexes and female rat formed 2 alpha- and 2 beta-OHP, while microsomes isolated from male rat formed exclusively 2 alpha-OHP. 7 alpha-Hydroxylation was detected exclusively in rat, and 6 alpha-hydroxylation was detected in both dog and rat. 17 alpha-Hydroxylase activity in primates was detected only in microsomes from male human. IC50 values associated with ketoconazole inhibition of progesterone metabolism differed among species.(ABSTRACT TRUNCATED AT 250 WORDS)
Swinney
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DC
Department of Drug Metabolism, Syntex Research, Palo Alto, CA 94304.
D058891:5-alpha Reductase Inhibitors; D000293:Adolescent; D000328:Adult; D000726:Androgen Antagonists / Q000494:pharmacology*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001378:Azasteroids / Q000494:pharmacology*; D065727:Cytochrome P-450 CYP2C8; D065729:Cytochrome P-450 CYP2C9; D065607:Cytochrome P-450 Enzyme Inhibitors; D000072467:Cytochrome P450 Family 2; D013196:Dihydrotestosterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D004285:Dogs; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007654:Ketoconazole / Q000494:pharmacology*; D008252:Macaca fascicularis; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D011374:Progesterone / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D039181:Steroid 16-alpha-Hydroxylase
D058891:5-alpha Reductase Inhibitors; D000726:Androgen Antagonists; D001378:Azasteroids; D065607:Cytochrome P-450 Enzyme Inhibitors; D013196:Dihydrotestosterone; D011374:Progesterone; C031563:17-N,N-diethylcarbamoyl-4-methyl-4-azaandrostane-3-one; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D007654:Ketoconazole