Transformations of DHEA and its metabolites by rat liver

Abstract

Because dehydroepiandrosterone (DHEA) has a wide variety of weak beneficial effects in experimental animals and humans, we searched for metabolites of this steroid in the hope of finding more active compounds that might qualify for the title "steroid hormone." Incubation of DHEA with rat liver homogenate fortified with energy-yielding substrates resulted in rapid hydroxylation at the 7alpha-position of the molecule and subsequent conversion to other 7-oxygenated steroids in the sequence DHEA --> 7alpha-hydroxyDHEA --> 7-oxoDHEA --> 7beta-hydroxyDHEA, with branching to diols, triols, and sulfate esters. The ability of these metabolites to induce the formation of liver thermogenic enzyme activity increased from left to right in that sequence. A total of 25 different steroids were characterized, and at least six additional structures that are currently under study were produced from DHEA. 7-OxoDHEA is more effective than DHEA in enhancing memory performance in old mice and in reversing the amnesic effects of scopolamine.

The identification and simultaneous quantification of 7-hydroxylated metabolites of pregnenolone, dehydroepiandrosterone, 3β,17β-androstenediol, and testosterone in human serum using gas chromatography–mass spectrometry

“…The findings for DHEA support the recently reported model suggesting 7␣-hydroxylation of the parent steroid, reversible conversion of the product to a 7-oxointermediate, and finally conversion to the 7␤-hydroxylated metabolite [28,46].…”

“…For the 7␤-hydroxylated metabolites of Preg, the results in women also were consistent with the reported model [28,46], with both pair and partial correlations being significant. In men, a significant pair correlation was found, but an insignificant partial correlation was found between Preg7a and Preg7b, indicating the lesser importance of substrate concentration in product formation.…”

“…In women, the corresponding pair correlation was strong and significant, but the partial correlation not. Accordingly, in contrast to men, AT7a levels are not crucial to AT7b formation, but the result may still be in accordance with the aforementioned model [28,46].…”

Effect of dehydroepiandrosterone (DHEA) treatment on oxidative energy metabolism in rat liver and brain mitochondria. A dose–response study

“…However, inhibition of state 3 respiration rate and FoF 1 ATPase activity in mitochondria by addition of DHEA and DHEA-S in vitro [29,30,31] would argue against this possibility. Alternative mechanism that has been proposed is that secondary metabolites, steroid in nature, may mediate DHEA action [32]. More recently, it has been demonstrated that DHEA is metabolized to 7α-hydroxy-DHEA and δ5-androstene-3β,17β-diol.…”

Mitotic and neurogenic effects of dehydroepiandrosterone (DHEA) on human neural stem cell cultures derived from the fetal cortex

“…DHEA is readily converted metabolically to derivatives that are more active in some assays (24,30,31). In rat liver homogenate, the sequence is DHEA 3 7␣-OH-DHEA 3 7-oxo-DHEA 3 7␤-OH-DHEA 3 androst-5-en-3␤,7␤,17␤-triol.…”