An important requirement for physiologic homeostasis is the detoxification and removal of endogenous hormones and xenobiotic compounds with biological activity. Much of the detoxification is performed by cytochrome 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 metabolic pathway. Instead of possessing hundreds of receptors, one for each inducing compound, we propose the existence of a few broad specificity, low-affinity sensing receptors that would monitor aggregate levels of inducers to trigger production of metabolizing enzymes. In support of this model, we have isolated a novel nuclear receptor, termed the steroid and xenobiotic receptor (SXR), which activates transcription in response to a diversity of natural and synthetic compounds. SXR forms a heterodimer with RXR that can bind to and induce transcription from response elements present in steroid-inducible cytochrome P-450 genes and is expressed in tissues in which these catabolic enzymes are expressed. These results strongly support the steroid sensor hypothesis and suggest that broad specificity sensing receptors may represent a novel branch of the nuclear receptor superfamily.[Key Words: Steroid; xenobiotic receptor; nuclear receptor; transcriptional activity] Received July 24, 1998; revised version accepted August 26, 1998. Lipophilic hormones, such as steroids, retinoic acid, thyroid hormone, and vitamin D3, control broad aspects of animal growth, development, and adult organ physiology. The effects of these hormones are mediated by a large superfamily of intracellular receptors that function as ligand-dependent and sequence-specific transcription factors. The nonsteroidal nuclear receptors for thyroid hormone (TR), vitamin D3 (VDR), all-trans retinoic acid (RAR), and fatty acids and eicosanoids (PPAR) form heterodimers with the 9-cis retinoic acid receptor (RXR) that bind bipartite hormone-response elements (HREs) composed of directly repeated half sites related to the sequence AGGTCA (Mangelsdorf and Evans 1995). In contrast, the steroid receptors function as homodimers and bind to palindromic target sequences spaced by three nucleotides . In addition to the known receptors, a large group of structurally related 'orphan' nuclear receptors has been described; that these receptors possess obvious DNA and ligand-binding domains but lack identified ligands . Each has the potential to regulate a distinct endocrine signaling pathway.It is widely viewed that the hormone response is a consequence of the release from an endocrine gland of a ligand that circulates through the blood, and coordinately regulates responses in target tissues by acting through specific nuclear receptors. Hormone responsiveness is dependent on the ability to rapidly clear ligand from the blood and the body so that, in absence of a stimulus, target tissues re...