title: Self-augmentation effect of male-specific products on sexually differentiated progesterone metabolism in adult male rat liver microsomes.
abstract: It is well known that several 3-keto-4-ene steroids such as progesterone and testosterone are metabolized in a gender-specific or -predominant manner by adult rat liver microsomes. In the male, these steroids are primarily metabolized into two oxidized (16alpha-hydroxyl and 6beta-hydroxyl) products mainly by the respective, male-specific cytochrome P450 subforms, CYP2C11 and CYP3A2, while they are primarily metabolized into the 5alpha-reduced products by female-predominant 5alpha-reductase in the female. These sexually differentiated enzyme activities are largely regulated at the transcription level under endocrine control. In the present study, we show that unlabeled 16alpha-hydroxyprogesterone and 6beta-hydroxyprogesterone inhibited the 5alpha-reductive [(3)H]progesterone metabolism by adult male rat liver microsomes without significantly inhibiting the CYP2C11 and CYP3A2 activities producing themselves, whereas 3alpha-hydroxy-5alpha-pregnan-20-one and 5alpha-pregnane-3,20-dione not only stimulated the 5alpha-reductive metabolism producing themselves but also inhibited the male-specific oxidative metabolism. This finding compels us to propose a novel hypothesis that adult male rat liver microsomes may possess a self-augmentation system regulated by the male-specific products on sexually differentiated steroid metabolism, besides regulation by gene expressions of the related enzymes.
authors.affiliation: Second Department of Pathology, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan. a-yamada@hyo-med.ac.jp
authors.forename: A
authors.initials: A
authors.lastname: Yamada
authors.forename: M
authors.initials: M
authors.lastname: Yamada
authors.forename: Y
authors.initials: Y
authors.lastname: Fujita
authors.forename: T
authors.initials: T
authors.lastname: Nishigami
authors.forename: K
authors.initials: K
authors.lastname: Nakasho
authors.forename: K
authors.initials: K
authors.lastname: Uematsu
mesh_terms: D043582:5-alpha-Dihydroprogesterone; D000818:Animals; D000906:Antibodies / Q000276:immunology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006908:Hydroxyprogesterones / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D008954:Models, Biological; D009251:NADPH-Ferrihemoprotein Reductase / Q000276:immunology; D010084:Oxidation-Reduction; D011277:Pregnanediones / Q000494:pharmacology; D011280:Pregnanolone / Q000494:pharmacology; D011374:Progesterone / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012727:Sex Characteristics; D013250:Steroid Hydroxylases / Q000378:metabolism
chemical_list: D000906:Antibodies; D006908:Hydroxyprogesterones; D011277:Pregnanediones; C018975:16-hydroxyprogesterone; D011374:Progesterone; C048534:6-hydroxyprogesterone; D003577:Cytochrome P-450 Enzyme System; D043582:5-alpha-Dihydroprogesterone; D011280:Pregnanolone; D013250:Steroid Hydroxylases; C022657:steroid hormone 6-beta-hydroxylase; D009251:NADPH-Ferrihemoprotein Reductase