title: Regulation of endobiotics glucuronidation by ligand-activated transcription factors: physiological function and therapeutic potential.
abstract: Recent progresses in molecular pharmacology approaches have allowed the identification and characterization of a series of nuclear receptors (NR) which efficiently control the level UDP-glucuronosyltransferase (UGT) genes expression. These regulatory processes ensure optimized UGT expression in response to specific endogenous and/or exogenous stimuli. Interestingly, numerous endogenous activators of these NRs are conjugated by the UGT enzymes they regulate. In such a case, the NR-dependent regulation of UGT genes corresponds to a feedforward/feedback mechanism by which a bioactive molecule controls its own concentrations. In the present review, we will discuss i) how bilirubin reduces its circulating levels by activating AhR in the liver; ii) how bile acids modulate their hepatic glucuronidation via PXR- and FXR-dependent processes in enterohepatic tissues; and iii) how androgens inhibit their cellular metabolism in prostate cancer cells through an AR-dependent mechanism. Subsequently, with further discussion of the same examples (bilirubin and bile acids), we will illustrate how NR-dependent regulation of UGT enzymes may contribute to the beneficial effects of pharmacological activators of nuclear receptors, such as CAR and PPARa.
authors.affiliation: Laboratory of Molecular Pharmacology, CHUQ Research Center and Faculty of Pharmacy, Laval University, Québec, Canada.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Verreault
authors.forename: Jenny
authors.initials: J
authors.lastname: Kaeding
authors.forename: Patrick
authors.initials: P
authors.lastname: Caron
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Trottier
authors.forename: Laurent
authors.initials: L
authors.lastname: Grosse
authors.forename: Elise
authors.initials: E
authors.lastname: Houssin
authors.forename: Sophie
authors.initials: S
authors.lastname: Pâquet
authors.forename: Martin
authors.initials: M
authors.lastname: Perreault
authors.forename: Olivier
authors.initials: O
authors.lastname: Barbier
mesh_terms: D051696:Activating Transcription Factors / Q000378:metabolism / Q000502:physiology*; D001647:Bile Acids and Salts / Q000378:metabolism*; D001663:Bilirubin / Q000097:blood*; D002478:Cells, Cultured; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D051696:Activating Transcription Factors; D001647:Bile Acids and Salts; D020719:Glucuronides; D018160:Receptors, Cytoplasmic and Nuclear; D014453:Glucuronosyltransferase; D001663:Bilirubin