The Salk Institute

Wen Xie

Ronald Mark Evans

Bruce Blumberg

In accordance with the present invention, there are provided methods for modulating Phase II conjugating enzymes such as, for example, UGTs. Phase II conjugating enzymes such as UGTs function in concert with Phase I monooxygenase enzymes such as cytochrome P450 enzymes (CYPs) to eliminate steroids and xenobiotics. Nuclear receptors SXR/PXR and CAR are xenosensors regulating expression of CYP genes such as CYP3A and 2B. The ability of this group of receptors to regulate expression of UGT in response to steroids and/or xenobiotics provides novel approaches for direct regulation/activation of a glucuronidation pathway, thereby providing methods to achieve physiologic homeostasis with respect to steroids and/or xenobiotics. SXR/PXR and CAR regulation/activation of UGT represents the first evidence of receptors that can transduce/transactivate both Phase I and Phase II adaptive hepatic response. In another aspect, the present invention also provides transgenic rodents expressing one or more of SXR, CAR or PXR.

Modulation of metabolism of steroids and xenobiotics

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.

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Wen Xie