GLUCURONIDATION: THE LAST DEFENSIVE LINE AGAINST BILEACID TOXICITY DURING CHOLESTASIS.

Abstract

Glucuronidation is a detoxification reaction for bile acids (BA). The present study evaluates its efficiency to protect liver cells during acute (biliary obstruction, BO) and chronic (primary biliary cholangitis, PBC and primary sclerosing cholangitis, PSC) cholestatic situations. BA-glucuronides (G) were first profiled in sera from control, PBC, PSC and BO donors. An impressive accumulation of BA-Gs, formed from toxic BAs, is observed in sera from BO patients. Liver samples from control, PBC, or PSC donors and human hepatic cells were exposed to BAs, BA-G, agonists of the BA sensors Pregnane X-Receptor (PXR) or Farnesoid X-Receptor (FXR) and were analyzed for the expression of BA-conjugating UDP-glucuronosyltransferase (UGT) enzymes using quantitative RT-PCR and/or immnunoblot. Expression of the BA-conjugating UGT1A3, 1A4, and 2B4 enzymes was increased in hepatocytes exposed to BA levels mimicking BO. PXR activation also induced expression of the 3 UGTs, while FXR agonists only activated the UGT1A4 and 2B4 genes. Gelshift and luciferase transfection assays identified PXR response elements within UGT1A3 and 1A4 gene promoters. Finally, Inflammation markers have been reduced in hepatocytes treated with BA-G instead of BA. ConclusionThe present study identifies glucuronidation as a self-defense mechanism against BA toxicity during cholestasis. While of limited efficiency by itself, this endogenous mechanism is proposed as a novel pharmacological target in the treatment of chronic cholestatic diseases.