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A novel constitutive androstane receptor-mediated and CYP3A-independent pathway of bile acid detoxification.

Abstract：

: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.

journal_name

Mol Pharmacol

journal_title

Molecular pharmacology

authors

Saini SP,Sonoda J,Xu L,Toma D,Uppal H,Mu Y,Ren S,Moore DD,Evans RM,Xie W

doi

10.1124/mol.65.2.292

keywords:

subject

Has Abstract

pub_date

2004-02-01 00:00:00

pages

292-300

issue

2

eissn

0026-895X

issn

1521-0111

pii

65/2/292

journal_volume

65

pub_type

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