ISSN:
1365-2826
Source:
Blackwell Publishing Journal Backfiles 1879-2005
Topics:
Medicine
Notes:
Presently, several works question the effects of dehydroepiandrosterone (DHEA) reported in vivo and designate its 7-hydroxylated metabolites as native antiglucocorticoids and potent mediators in the triggering of immune response. Among mouse tissues and organs, and second to liver, the largest production of 7α-and 7β-hydroxylated derivatives of DHEA takes place in brain microsomes. To contribute to identification of cytochromes P450 (CYPs) responsible for 7α- and 7β-hydroxy-DHEA production, effects of CYP inhibitors and of several steroid hormones on DHEA 7-hydroxylation were examined. Using mouse brain microsomes as a source of enzyme, we report now that strong and smaller inhibitions of DHEA 7α-hydroxylation were obtained with ketoconazole and α-naphthoflavone, respectively, and that neither changed DHEA 7β-hydroxylation. Metyrapone and antipyrine also inhibited 7α-hydroxylation, but by contrast, significantly increased 7β-hydroxylation of DHEA. This indicated that at least, two different CYPs were responsible for 7α- and 7β-hydroxylation of DHEA. Steroids sharing a 3β-hydroxylated structure with DHEA, namely pregnenolone, 5-androstene-3β,17β-diol and 3β-hydroxy-5α-androstan-17-one, were strong inhibitors of DHEA 7α-hydroxylation (non-competitive inhibition with pregnenolone, Ki=2.0±0.3 μM). In contrast, 7β-hydroxylation yields were not decreased by the 3β-hydroxysteroids tested. Moderate inhibition of 7α- and 7β-hydroxylation was obtained with 3-oxosteroids, namely testosterone, progesterone, corticosterone and 4-androsten-3,17-dione. Taken together, these data indicate specific inhibition patterns of DHEA 7α- and 7β-hydroxylation by CYP inhibitors and steroid hormones in mouse brain microsomes and may be used as criteria necessary for identification of the responsible CYP species.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1046/j.1365-2826.1997.00661.x
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