An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids.
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.
Howard Hughes Medical Institute, Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
W
W
Xie
A
A
Radominska-Pandya
Y
Y
Shi
C M
CM
Simon
M C
MC
Nelson
E S
ES
Ong
D J
DJ
Waxman
R M
RM
Evans
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001647:Bile Acids and Salts / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus; D002522:Chlorocebus aethiops; D002779:Cholestasis / Q000378:metabolism* / Q000473:pathology; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004790:Enzyme Induction; D006801:Humans; D008095:Lithocholic Acid / Q000008:administration & dosage / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D000077297:Pregnane X Receptor; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D011987:Receptors, Steroid / Q000502:physiology*; D013379:Substrate Specificity
D001647:Bile Acids and Salts; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D008095:Lithocholic Acid; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating