CYP7B1‐mediated metabolism of dehydroepiandrosterone and 5α‐androstane‐3β,17β‐diol – potential role(s) for estrogen signaling

Abstract

CYP7B1, a cytochrome P450 enzyme, metabolizes several steroids involved in hormonal signaling including 5alpha-androstane-3beta,17beta-diol (3beta-Adiol), an estrogen receptor agonist, and dehydroepiandrosterone, a precursor for sex hormones. Previous studies have suggested that CYP7B1-dependent metabolism involving dehydroepiandrosterone or 3beta-Adiol may play an important role for estrogen receptor beta-mediated signaling. However, conflicting data are reported regarding the influence of different CYP7B1-related steroids on estrogen receptor beta activation. In the present study, we investigated CYP7B1-mediated conversions of dehydroepiandrosterone and 3beta-Adiol in porcine microsomes and human kidney cells. As part of these studies, we compared the effects of 3beta-Adiol (a CYP7B1 substrate) and 7alpha-hydroxy-dehydroepiandrosterone (a CYP7B1 product) on estrogen receptor beta activation. The data obtained indicated that 3beta-Adiol is a more efficient activator, thus lending support to the notion that CYP7B1 catalysis may decrease estrogen receptor beta activation. Our data on metabolism indicate that the efficiencies of CYP7B1-mediated hydroxylations of dehydroepiandrosterone and 3beta-Adiol are very similar. The enzyme catalyzed both reactions at a similar rate and the K(cat)/K(m) values were in the same order of magnitude. A high dehydroepiandrosterone/3beta-Adiol ratio in the incubation mixtures, similar to the ratio of these steroids in many human tissues, strongly suppressed CYP7B1-mediated 3beta-Adiol metabolism. As the efficiencies of CYP7B1-mediated hydroxylation of dehydroepiandrosterone and 3beta-Adiol are similar, we propose that varying steroid concentrations may be the most important factor determining the rate of CYP7B1-mediated metabolism of dehydroepiandrosterone or 3beta-Adiol. Consequently, tissue-specific steroid concentrations may have a strong impact on CYP7B1-dependent catalysis and thus on the levels of different CYP7B1-related steroids that can influence estrogen receptor beta signaling.

The androgen metabolite 5α-androstane-3β,17β-diol (3βAdiol) induces breast cancer growth via estrogen receptor: implications for aromatase inhibitor resistance

“…It has been known for some time that 3βAdiol can bind to both ERα and ERβ with approximately 30-fold and 14-fold lower affinity relative to that of E2, respectively, suggesting slight specificity for ERβ [13]. 3βAdiol has been extensively characterized as an ERβ ligand in in vitro ERβ-promoter driven luciferase assays [18,19], gene expression assays [20,21], and in vivo prostate and prostate cancer models [22,23]. 3βAdiol has been shown to play a well defined role in prostate cancer etiology as an ERβ ligand.…”

CYP7B1: One Cytochrome P450, Two Human Genetic Diseases, and Multiple Physiological Functions

“…One report suggested that this steroid was made in human prostatic cells and therein activated the receptor (23), whereas a second report failed to replicate the receptor activation in human embryonic kidney 293 cells (24). Both studies relied on in vitro transfection approaches, and to date, there is no in vivo evidence to suggest a physiological role for 7␣-hydroxylated dehydroepiandrosterone in estrogen receptor function.…”

Transformation of a series of saturated isomeric steroidal diols by Aspergillus tamarii KITA reveals a precise stereochemical requirement for entrance into the lactonization pathway

“…This is of significance due to the importance of hydrogen bonding in steroid/enzyme interactions [8][9][10][11][12][13][14][15][16] and in determining if specific stereochemistry is handled within different metabolic pathways. We have also modified a previous [17] synthetic strategy to facilitate an expedient route to 3␣-hydroxy containing 17␣-and 17␤-diols that, as with the other analogues [18][19][20][21][22][23] have a broad range of interesting biological activity in their own right [24][25][26][27].…”