cyp7b1 catalyses the 7α-hydroxylation of dehydroepiandrosterone and25-hydroxycholesterol in rat prostate

Abstract

Dehydroepiandrosterone (DHEA) is the most prominent circulating steroid in humans, and it is a precursor for sex-steroid synthesis in peripheral tissues, including the prostate. Recently, enzyme-mediated pre-receptor metabolism has been recognized as a key step in determining steroid action in vivo. Hydroxylation of 3beta-steroids at the 7alpha-position has been reported in rat and human prostate to be a major inhibitory pathway to sex-steroid synthesis/action. However, the molecular identity of the enzyme responsible is so far unknown. We recently described a novel cytochrome P450 enzyme, cyp7b1, strongly expressed in the hippocampus of rodent brain, which catalyses the metabolism of DHEA, pregnenolone and 25-hydroxycholesterol to 7alpha-hydroxy products. In the light of this new enzyme, we have examined its possible role in 7alpha-hydroxylation conversion in rat prostate. NADPH-dependent 7alpha-hydroxylation was confirmed for 3beta-hydroxysteroids including DHEA and androstenediol, as well as 25-hydroxycholesterol. Kinetic analysis yielded an apparent K(m) of 14+/-1 microM for 7alpha-hydroxylation of DHEA in the prostate gland, a value similar to that recorded for recombinant cyp7b1 enzyme [13.6 microM; Rose, Stapleton, Dott, Kieny, Best, Schwarz, Russell, Bjoorkheim, Seckl and Lathe (1997) Proc. Natl. Acad. Sci. U.S.A. 94, 4925-4930]. The V(max) value of the prostate was 46+/-2 pmol/min per mg, and this activity was inhibited by clotrimazole, a P450-enzyme blocker. Moreover, RNA analysis (reverse-transcription PCR, Northern blotting and in situ hybridization) revealed a high expression of cyp7b1 mRNA in the rat prostate, restricted to the epithelium, suggesting that cyp7b1 catalyses oxysterol 7alpha-hydroxylation in the prostate gland.

Sterol metabolism modulates susceptibility to HIV-1 Infection

“…The CYP7B1 gene encodes an enzyme that is involved in cholesterol catabolism by inactivation of oxysterols [63] but it also controls numerous immune functions, via its catabolite 25HC [64]. Notably, one of such effect is IgA synthesis [65], a class of antibodies previously associated with resistance to HIV-1-infection [66,67].…”

Men and women differ in their diurnal expression of monocyte peroxisome proliferator‐activated receptor‐α in the fed but not in the fasted state

“…Data from mouse studies indicate some fundamental interaction between PPARα and sex hormones. It has been shown in mice that PPARα is involved in estrogen signaling and reproduction (30–32). Conversely, female rats treated with testosterone and male rats treated with estrogen altered their mRNA concentration of PPARα (33).…”

The interaction between metabolism, cancer and cardiovascular disease, connected by 27-hydroxycholesterol

“…CYP7B1 is expressed in the brain, particularly in the hippocampus, but is also expressed in liver and other peripheral organs [20,21]. Although the physiological concentration of these substrates should be considered, CYP7B1 has a relatively broad substrate specificity for steroids and sterols such as dehydroepiandrosterone (DHEA), 5α-androstane-3β, 17β-diol (3Adiol), 25-hydroxycholesterol, pregnenorone, 17β-estradiol (E 2 ) and 27HC, as a 7α-hydroxylase [21–23]. Clinically, the importance of CYP7B1 has been reported in prostate cancer together with ER-β and 3Adiol because of its enzymatic function against androgen and estrogen, and CYP7B1 inhibitors can be used as chemoprevention and in the treatment of prostate cancer [23–25].…”