An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids

doi:10.1073/pnas.051014398

An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids

^§Howard Hughes Medical Institute, ^*Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037; ^†Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205; and ^‡Department of Biology, Division of Cell and Molecular Biology, Boston University, Boston, MA 02215

Contributed by Ronald M. Evans

Abstract

Hepatic hydroxylation is an essential step in the metabolism and excretion of bile acids and is necessary to avoid pathologic conditions such as cholestasis and liver damage. In this report, we demonstrate that the human xenobiotic receptor SXR (steroid and xenobiotic receptor) and its rodent homolog PXR (pregnane X receptor) serve as functional bile acid receptors in both cultured cells and animals. In particular, the secondary bile acid derivative lithocholic acid (LCA) is highly hepatotoxic and, as we show here, a metabolic substrate for CYP3A hydroxylation. By using combinations of knockout and transgenic animals, we show that activation of SXR/PXR is necessary and sufficient to both induce CYP3A enzymes and confer resistance to toxicity by LCA, as well as other xenotoxicants such as tribromoethanol and zoxazolamine. Therefore, we establish SXR and PXR as bile acid receptors and a role for the xenobiotic response in the detoxification of bile acids.

Footnotes

↵ ¶ To whom correspondence should be addressed. E-mail: evans{at}salk.edu.
Abbreviations:

CDCA,

chenodeoxycholic acid;

CYP,

cytochrome P450 enzyme;

DCA,

deoxycholic acid;

FXR,

farnesoid X receptor;

LCA,

lithocholic acid;

PCN,

pregnane-16α-carbonitrile;

PXR,

pregnane X receptor;

RIF,

rifampicin;

SXR,

steroid and xenobiotic receptor