Metabolic Transformations of Dehydroepiandrosterone

Abstract

Dehydroepiandrosterone (DHEA) is the most abundant steroid in the human body. It enhances the action of insulin, depresses the action of glucocorticoids, increases the activity of the immune system, and decreases body fat in genetically predisposed animals without affecting food intake. It is reported to have anti-carcinogenic and anti-viral activity. Relatively, large doses of DHEA are needed to obtain these effects indicating that metabolites of DHEA may be responsible for these activities. Mammalian tissues convert DHEA to the following in sequence: 7α-hydroxyDHEA, 7-oxoDHEA, 7β-hydroxyDHEA, 7β,16α-dihydroxyDHEA. A major metabolite is androstene-3β,17β-diol which we found to be an androgen that resists conventional anti-androgen drugs (PNAS 95:11083, 98). It very likely is responsible for prostate cancer growth in the so-called “androgen-independent”, fatal stage. Like the thermogenic thyroid hormone, DHEA and its metabolites induce the formation of two thermogenic enzymes - mitochondrial L-glycerophosphate dehydrogenase and cytosolic malic enzyme, that transfer electrons from reduced pyridine coenzymes to ubiquinone without accompanying phosphorylation. In enzyme induction assays, the metabolites are increasingly effective in the order of formation shown above. 16α-Hydroxylation destroys the activity of DHEA and androstenediol by preventing their conversion to active hormone structures, but enhances activity of 7-oxoDHEA. 16α-Bromination has effects like those exerted by hydroxylation. (Supported by the authors)