RT Journal Article
SR Electronic
T1 A Novel Constitutive Androstane Receptor-Mediated and CYP3A-Independent Pathway of Bile Acid Detoxification
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 292
OP 300
DO 10.1124/mol.65.2.292
VO 65
IS 2
A1 Simrat P. S. Saini
A1 Junichiro Sonoda
A1 Li Xu
A1 David Toma
A1 Hirdesh Uppal
A1 Ying Mu
A1 Songrong Ren
A1 David D. Moore
A1 Ronald M. Evans
A1 Wen Xie
YR 2004
UL http://molpharm.aspetjournals.org/content/65/2/292.abstract
AB Cytosolic sulfotransferase (SULT)-mediated sulfation plays an essential role in the detoxification of bile acids and is necessary to avoid pathological conditions, such as cholestasis, liver damage, and colon cancer. In this study, using transgenic mice bearing conditional expression of the activated constitutive androstane receptor (CAR), we demonstrate that activation of CAR is both necessary and sufficient to confer resistance to the hepatotoxicity of lithocholic acid (LCA). Surprisingly, the CAR-mediated protection is not attributable to the expected and previously characterized CYP3A pathway; rather, it is associated with a robust induction of SULT gene expression and increased LCA sulfation. We have also provided direct evidence that CAR regulates SULT expression by binding to the CAR response elements found within the SULT gene promoters. Interestingly, activation of CAR was also associated with an increased expression of the 3′-phosphoadenosine 5′-phosphosulfate synthetase 2 (PAPSS2), an enzyme responsible for generating the sulfate donor 3′-phosphoadenosine-5′-phosphosulfate. Analysis of gene knockout mice revealed that CAR is also indispensable for ligand-dependent activation of SULT and PAPSS2 in vivo. Therefore, we establish an essential and unique role of CAR in controlling the mammalian sulfation system and its implication in the detoxification of bile acids.