SXR, A NOVEL STEROID AND XENOBIOTIC-SENSING NUCLEAR RECEPTOR

An important requirement for physiologic homeostasis is the detoxifica tion and removal of endogenous hormones and xenobiotic compounds with biological activity. Much of the detoxification is performed by cytoch rome P-450 enzymes, many of which have broad substrate specificity and are inducible by hundreds of different compounds, including steroids. The ingestion of dietary steroids and lipids induces the same enzymes ; therefore, they would appear to be integrated into a coordinated met abolic pathway. Instead of possessing hundreds of receptors, one for e ach inducing compound, we propose the existence of a few broad specifi city, low-affinity sensing receptors that would monitor aggregate leve ls of inducers to trigger production of metabolizing enzymes. In suppo rt of this model, rye have isolated a novel nuclear receptor, termed t he steroid and xenobiotic receptor (SXR), which activates transcriptio n in response to a diversity of natural and synthetic compounds. SXR f orms a heterodimer with RXR that can bind to and induce transcription from response elements present in steroid-inducible cytochrome P-450 g enes and is expressed in tissues in which these catabolic enzymes are expressed. These results strongly support the steroid sensor hypothesi s and suggest that broad specificity sensing receptors may represent a novel branch of the nuclear receptor superfamily.