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.

Keywords::

• Constitutive androstane receptor (CAR)
• aryl hydrocarbon receptor (AhR)
• farnesoid X-receptor (FXR)
• pregnane X-receptor (PXR)
• androgen receptor (AR)
• peroxisome proliferator-activated receptor-a (PPARa)
• bilirubin
• bile acids
• androgens

Acknowledgments

Research at the Laboratory of Molecular Pharmacology is supported by grants from the Canadian Institute of Health Research (CIHR; grant #MOP-84338 & MOP-97866) the Canadian Foundation for Innovation (CFI, grant #10469 and 17745). JT and the Pfizer Cardiovascular is the holder of a scholarship from CIHR, MP and SP are funded by grants from the “Fonds de la Recherche en Santé du Québec,” and EH by the “Fonds pour L’Enseignement et la Recherche de la Faculté de Pharmacie de l’Université Laval.” OB is the holder of a salary grant from the CIHR (New investigator award #MSH95330).

Declaration of interest: The authors declare that there no conflicts of interest.