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 chole stasis and liver damage. In this report, we demonstrate that the human xeno biotic receptor SXR (steroid and xenobiotic receptor) and its rodent homolo g PXR (pregnane X receptor) serve as functional bile acid receptors in both cultured cells and animals. In particular, the secondary bile acid derivat ive lithocholic acid (LCA) is highly hepatotoxic and, as we show here, a me tabolic substrate far CYP3A hydroxylation. By using combinations of knockou t and transgenic animals, we show that activation of SXR/PXR is necessary a nd sufficient to both induce CYP3A enzymes and confer resistance to toxicit y by LCA, as well as other xenotoxicants such as tribromoethanol and zoxazo lamine. Therefore, we establish SXR and PXR as bile acid receptors and a ro le for the xenobiotic response in the detoxification of bile acids.