Pharmacology and immune modulating properties of 5-androstene-3ß,7ß,17ß-triol, a DHEA metabolite in the human metabolome.

ABSTRACT

Androst-5-ene-3ß,7ß,17ß-triol (ßAET) is an anti-inflammatory metabolite of DHEA that is found naturally in humans, but in rodents only after exogenous DHEA administration. Unlike DHEA, C-7-oxidized DHEA metabolites cannot be metabolized into potent androgens or estrogens, and are not peroxisome proliferators in rodents. The objective of our current studies was to characterize the pharmacology of ßAET to enable clinical trials in humans. The pharmacology of ßAET was characterized by pharmacokinetics, drug metabolism, nuclear hormone receptor interactions, androgenicity, estrogenicity, and systemic toxicity studies. ßAET's acute anti-inflammatory activity and immune modulating characteristics were measured in vitro in RAW264.7 cells and in vivo in murine models with parenteral administration. ßAET was rapidly metabolized and cleared from circulation in mice and monkeys. ßAET was weakly androgenic and estrogenic in immature rodents, but not bound by androgen, estrogen, progesterone, or glucocorticoid nuclear hormone receptors. ßAET did not induce peroxisome proliferation, nor was it systemically toxic or trophic for sex hormone responsive tissues in mature rats and monkeys. ßAET significantly attenuated acute inflammation both in vitro and in vivo, augmented immune responses in adult mice, and reversed immune senescence in aged mice. ßAET may contribute to the anti-inflammatory activity in rodents attributed to DHEA. Unlike DHEA, ßAET's anti-inflammatory activity cannot be ascribed to activation of PPARs, androgen, or estrogen nuclear hormone receptors. Exogenous ßAET is unlikely to produce untoward toxicity or hormonal perturbations in humans.