Reciprocal activation of Xenobiotic response genes by nuclear receptors SXR/PXR and CAR

The cytochrome P450 (CYP) gene products such as CYP3A and CYP2B are essenti al for the metabolism of steroid hormones and xenochemicals including presc ription drugs. Nuclear receptor SXR/PXR (steroid and xenobiotic receptor/pr egnenolone X receptor) has been shown both biochemically and genetically to activate CM3A genes, while similar studies have established constitutive a ndrostane receptor (CAR) as a CYP2B regulator. The response elements in the se genes are also distinct, furthering the concept of independent regulatio n. Unexpectedly, we found that SXR can regulate CYP2B, both in cultured cel ls and in transgenic mice via adaptive recognition of the phenobarbital res ponse element (PBRE). In a type of functional symmetry, orphan receptor CAR was also found to activate CYP3A through previously defined SXR/PXR respon se elements. These observations not only provide a rational explanation for the activation of multiple CYP gene classes by certain xenobiotics, but al so reveal the existence of a metabolic safety net that confers a second lay er of protection to the harmful effects of toxic compounds and at the same time increases the propensity for drug-drug interactions.