title: Multiple roles for UDP-glucuronosyltransferase (UGT)2B15 and UGT2B17 enzymes in androgen metabolism and prostate cancer evolution.
abstract: In the prostate, approximately 50% of androgens are from adrenal steroids, mainly dehydroepiandrosterone (DHEA), its sulfate and androstenedione. These compounds are converted first into testosterone, and then into the active hormone dihydrotestosterone (DHT). After having activated the androgen receptor (AR), DHT is reduced into androstane-3α-DIOL (3α-DIOL) and androsterone (ADT), which are subsequently converted into 2 inactive and easily excretable metabolites: 3α-DIOL-17glucuronide (3α-DIOL-17G) and ADT-3glucuronide (ADT-3G). The formation of these last derivatives through the glucuronidation reaction involves 2 UDP-glucuronosyltransferase (UGT) enzymes, namely UGT2B15 and UGT2B17. The present review article aims at providing a comprehensive view of the physiological and pharmacological importance of these 2 enzymes for the control of androgen homeostasis. We will resume: (i) how UGT2B15 and UGT2B17 contribute to androgen elimination; (ii) how their glucuronidation capacity influences the androgen signaling pathway in prostate cells; (iii) how they contribute to the anti-proliferative properties of AR antagonists in prostate cancer cells; and (iv) how AR and its spliced variants regulate the UGT2B15 and/or UGT2B17 genes expression. Finally, whether the unexploited AR-UGT axis could serve as a prognostic maker or a pharmacological target for novel therapeutics in the treatment of prostate cancer is also discussed. This article is part of a special issue entitled 'Essential role of DHEA'.
authors.affiliation: Laboratory of Molecular Pharmacology, CHU de Québec Research Centre, and the Faculty of Pharmacy, Laval University, Québec, Canada.
authors.forename: Louis
authors.initials: L
authors.lastname: Gauthier-Landry
authors.affiliation: CHU de Québec Research Centre, and the Faculty of Medicine, Laval University, Québec, Canada.
authors.forename: Alain
authors.initials: A
authors.lastname: Bélanger
authors.affiliation: Laboratory of Molecular Pharmacology, CHU de Québec Research Centre, and the Faculty of Pharmacy, Laval University, Québec, Canada. Electronic address: olivier.barbier@crchul.ulaval.ca.
authors.forename: Olivier
authors.initials: O
authors.lastname: Barbier
mesh_terms: D000728:Androgens / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D015778:Minor Histocompatibility Antigens; D011379:Prognosis; D011467:Prostate / Q000201:enzymology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism
chemical_list: D000728:Androgens; D015778:Minor Histocompatibility Antigens; D011944:Receptors, Androgen; D014453:Glucuronosyltransferase; C472000:UDP-glucuronosyltransferase 2B15, human; C500513:UGT2B17 protein, human
keywords: Androgen deprivation therapy; Androgen metabolism; Androgen receptor; Glucuronidation; Prostate cancer; UDP-glucuronosyltransferase enzymes