CYP7B1-mediated metabolism of 5alpha-androstane-3alpha,17beta-diol (3alpha-Adiol): a novel pathway for potential regulation of the cellular levels of androgens and neurosteroids.
The current study presents data indicating that 5alpha-androstane-3alpha,17beta-diol (3alpha-Adiol) undergoes a previously unknown metabolism into hydroxymetabolites, catalyzed by CYP7B1. 3alpha-Adiol is an androgenic steroid which serves as a source for the potent androgen dihydrotestosterone and also can modulate gamma-amino butyric acid A (GABA(A)) receptor function in the brain. The steroid hydroxylase CYP7B1 is known to metabolize cholesterol derivatives, sex hormone precursors and certain estrogens, but has previously not been thought to act on androgens or 3alpha-hydroxylated steroids. 3alpha-Adiol was found to undergo NADPH-dependent metabolism into 6- and 7-hydroxymetabolites in incubations with porcine microsomes and human kidney-derived HEK293 cells, which are high in CYP7B1 content. This metabolism was suppressed by addition of steroids known to be metabolized by CYP7B1. In addition, 3alpha-Adiol significantly suppressed CYP7B1-mediated catalytic reactions, in a way as would be expected for substrates that compete for the same enzyme. Recombinant expression of human CYP7B1 in HEK293 cells significantly increased the rate of 3alpha-Adiol hydroxylation. Furthermore, the observed hydroxylase activity towards 3alpha-Adiol was very low or undetectable in livers of Cyp7b1(-/-) knockout mice. The present results indicate that CYP7B1-mediated catalysis may play a role for control of the cellular levels of androgens, not only of estrogens. These findings suggest a previously unknown mechanism for metabolic elimination of 3alpha-Adiol which may impact intracellular levels of dihydrotestosterone and GABA(A)-modulating steroids.
Pettersson
Hanna
H
Department of Pharmaceutical Biosciences, Division of Biochemistry, University of Uppsala, Biomedical Centre Box 578, S-751 23 Uppsala, Sweden.
Lundqvist
Johan
J
Oliw
Ernst
E
Norlin
Maria
M
D000728:Androgens / Q000378:metabolism*; D015113:Androstane-3,17-diol / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D055162:Biocatalysis; D002460:Cell Line; D000072474:Cytochrome P450 Family 7; D047629:Estrogen Receptor beta / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D013058:Mass Spectrometry; D053858:Metabolic Networks and Pathways; D051379:Mice; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000378:metabolism; D008954:Models, Biological; D009249:NADP / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000172:deficiency / Q000378:metabolism*; D034421:Sus scrofa
D000728:Androgens; D047629:Estrogen Receptor beta; D018377:Neurotransmitter Agents; D011944:Receptors, Androgen; D011994:Recombinant Proteins; D015113:Androstane-3,17-diol; D009249:NADP; D013250:Steroid Hydroxylases; D000072474:Cytochrome P450 Family 7; C499571:CYP7B1 protein, human; C097207:Cyp7b1 protein, mouse