Humanized xenobiotic response in mice expressing nuclear receptor SXR

The cytochrome CYP3A gene products, expressed in mammalian liver, are essen tial for the metabolism of lipophilic substrates, including endogenous ster oid hormones and prescription drugs(1,2). CYP3A enzymes are extremely versa tile and are inducible by many of their natural and xenobiotic substrates. Consequently, they form the molecular basis for many clinical drug-drug int eractions(3). The induction of CYP3A enzymes is species-specific(4,5), and we have postulated that it involves one or more cellular factors, or recept or-like xeno-sensors(6). Here we identify one such factor unequivocally as the nuclear receptor pregnenolone X receptor (PXR)(7,8) and its human homol ogue, steroid and xenobiotic receptor (SXR)(8-10). We show that targeted di sruption of the mouse PXR gene abolishes induction of CYP3A by prototypic i nducers such as dexamethasone or pregnenolone-16 alpha-carbonitrile. In tra nsgenic mice, an activated form of SXR causes constitutive upregulation of CYP3A gene expression and enhanced protection against toxic xenobiotic comp ounds. Furthermore, we show that the species origin of the receptor, rather than the promoter structure of CYP3A genes, dictates the species-specific pattern of CYP3A inducibility. Thus, we can generate 'humanized' transgenic mice that are responsive to human-specific inducers such as the antibiotic rifampicin. We conclude that SXR/PXR genes encode the primary species-spec ific xeno-sensors that mediate the adaptive hepatic response, and may repre sent the critical biochemical mechanism of human xenoprotection.