Sammanfattning

The current study presents data indicating that 5 alpha-androstane-3 alpha,17 beta-diol (3 alpha-Adiol) undergoes a previously unknown metabolism into hydroxymetabolites, catalyzed by CYP7B1. 3 alpha-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 3 alpha-hydroxylated steroids. 3 alpha-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, 3 alpha-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 3 alpha-Adiol hydroxylation. Furthermore, the observed hydroxylase activity towards 3 alpha-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 3 alpha-Adiol which may impact intracellular levels of dihydrotestosterone and GABA(A)-modulating steroids. (C) 2009 Elsevier B.V. All rights reserved.

Nyckelord

CYP7B1; 5 alpha-Androstane-3 alpha,17 beta-diol; Steroid metabolism; Androgen; Neurosteroid

Publicerad i

Biochimica et Biophysica Acta Molecular and Cell Biology of Lipids
2009, Volym: 1791, nummer: 12, sidor: 1206-1215

UKÄ forskningsämne

Neurovetenskaper
Farmaceutisk vetenskap
Farmakologi och toxikologi


Publikationens identifierare

DOI: https://doi.org/10.1016/j.bbalip.2009.08.010

Permanent länk till denna sida (URI)

https://res.slu.se/id/publ/88761