CYP7B1-mediated metabolism of 5 alfa-androstane-3 alfa,17 beta-diol (3 alfa-Adiol) : A novel pathway for potential regulation of the cellular levels of androgens and neurosteroids

• The current study presents data indicating that 5alfa-androstane-3alfa,17beta-diol (3alfa-Adiol) undergoes a previously unknown metabolism into hydroxymetabolites, catalyzed by CYP7B1. 3alfa-Adiol is an androgenic steroid which serves as a source for the potent androgen dihydrotestosterone and also can modulate gamma-amino butyric acid A (GABAA) 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 3a-hydroxylated steroids. 3alfa-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. Also, recombinant expression of human CYP7B1 in HEK293 cells significantly increased the rate of 3alfa-Adiol hydroxylation. In addition, 3alfa-Adiol significantly suppressed CYP7B1-mediated catalytic reactions, in a way as would be expected for substrates that compete for the same enzyme. 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 3alfa-Adiol which may impact intracellular levels of dihydrotestosterone and GABAA-modulating steroids.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)

Nyckelord

CYP7B1

5alfa-androstane-3alfa

17beta-diol

steroid metabolism

androgen

neurosteroid

PHARMACY

FARMACI

Biokemi

Biochemistry

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