Regulation of endobiotics glucuronidation by ligand-activated transcription factors: physiological function and therapeutic potential.
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.
Verreault
Mélanie
M
Laboratory of Molecular Pharmacology, CHUQ Research Center and Faculty of Pharmacy, Laval University, Québec, Canada.
Kaeding
Jenny
J
Caron
Patrick
P
Trottier
Jocelyn
J
Grosse
Laurent
L
Houssin
Elise
E
Pâquet
Sophie
S
Perreault
Martin
M
Barbier
Olivier
O
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
D051696:Activating Transcription Factors; D001647:Bile Acids and Salts; D020719:Glucuronides; D018160:Receptors, Cytoplasmic and Nuclear; D014453:Glucuronosyltransferase; D001663:Bilirubin