A novel constitutive androstane receptor-mediated and CYP3A-independent pathway of bile acid detoxification.
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.
Saini
Simrat P S
SP
Center for Pharmacogenetics, and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Sonoda
Junichiro
J
Xu
Li
L
Toma
David
D
Uppal
Hirdesh
H
Mu
Ying
Y
Ren
Songrong
S
Moore
David D
DD
Evans
Ronald M
RM
Xie
Wen
W
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000502:physiology*; D015239:Arylsulfotransferase; D001647:Bile Acids and Salts / Q000502:physiology*; D000090702:Constitutive Androstane Receptor; D051544:Cytochrome P-450 CYP3A; D005260:Female; D008658:Inactivation, Metabolic / Q000502:physiology; D008095:Lithocholic Acid / Q000493:pharmacokinetics / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013430:Sulfate Adenylyltransferase / Q000378:metabolism; D015238:Sulfotransferases / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
D001647:Bile Acids and Salts; D000090702:Constitutive Androstane Receptor; D009097:Multienzyme Complexes; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D008095:Lithocholic Acid; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; C022322:PAPS synthetase; D013430:Sulfate Adenylyltransferase; D015238:Sulfotransferases; D015239:Arylsulfotransferase; C117544:SULT1A1 protein, human; C513291:Sult1a1 protein, mouse