A novel nuclear receptor, termed the steroid and xenobiotic receptor (SXR), a
broad-specificity
sensing receptor that is a novel branch of the nuclear receptor superfamily, has
been discovered. SXR forms a heterodimer with RXR that can bind to and induce transcription
from response elements present in steroid-inducible cytochrome P450 genes in response
to hundreds of natural and synthetic compounds with biological activity, including
therapeutic steroids as well as dietary steroids and lipids. Instead of hundreds
of receptors, one for each inducing compound, the invention SXR receptors monitor
aggregate levels of inducers to trigger production of metabolizing enzymes in a
coordinated metabolic pathway. Agonists and antagonists of SXR are administered
to subjects to achieve a variety of therapeutic goals dependent upon modulating
metabolism of one or more endogenous steroids or xenobiotics to establish homeostasis.
An assay is provided for identifying steroid drugs that are likely to cause drug
interaction if administered to a subject in therapeutic amounts. Transgenic animals
are also provided which express human SXR, thereby serving as useful models for
human response to various agents which potentially impact P450-dependent metabolic
processes. Also provided are expression systems and expression vectors having SXR
receptors and the like operably linked to target genes of interest.
