title: Pharmacology and immune modulating properties of 5-androstene-3β,7β,17β-triol, a DHEA metabolite in the human metabolome.
abstract: Androst-5-ene-3β,7β,17β-triol (βAET) 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 βAET to enable clinical trials in humans. The pharmacology of βAET was characterized by pharmacokinetics, drug metabolism, nuclear hormone receptor interactions, androgenicity, estrogenicity, and systemic toxicity studies. βAET'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. βAET was rapidly metabolized and cleared from circulation in mice and monkeys. βAET was weakly androgenic and estrogenic in immature rodents, but not bound by androgen, estrogen, progesterone, or glucocorticoid nuclear hormone receptors. βAET did not induce peroxisome proliferation, nor was it systemically toxic or trophic for sex hormone responsive tissues in mature rats and monkeys. βAET significantly attenuated acute inflammation both in vitro and in vivo, augmented immune responses in adult mice, and reversed immune senescence in aged mice. βAET may contribute to the anti-inflammatory activity in rodents attributed to DHEA. Unlike DHEA, βAET's anti-inflammatory activity cannot be ascribed to activation of PPARs, androgen, or estrogen nuclear hormone receptors. Exogenous βAET is unlikely to produce untoward toxicity or hormonal perturbations in humans.
authors.affiliation: Harbor Biosciences, Inc., San Diego, CA 92122, United States. cahlem@harborbiosciences.com
authors.forename: Clarence N
authors.initials: CN
authors.lastname: Ahlem
authors.forename: Dominick L
authors.initials: DL
authors.lastname: Auci
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
authors.forename: Raymond
authors.initials: R
authors.lastname: Pieters
authors.forename: Michael R
authors.initials: MR
authors.lastname: Kennedy
authors.forename: Theodore M
authors.initials: TM
authors.lastname: Page
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Reading
authors.forename: Elena Y
authors.initials: EY
authors.lastname: Enioutina
authors.forename: James M
authors.initials: JM
authors.lastname: Frincke
mesh_terms: D000736:Androstenes / Q000378:metabolism; D000737:Androstenols / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D003687:Dehydroepiandrosterone / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007107:Immune System / Q000187:drug effects*; D007155:Immunologic Factors / Q000378:metabolism / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D055442:Metabolome / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D017208:Rats, Wistar
chemical_list: C108492:5-androstene-3,7,17-triol; D000736:Androstenes; D000737:Androstenols; D007155:Immunologic Factors; D003687:Dehydroepiandrosterone