Xie W, Barwick J L, Simon C M, Pierce A M, Safe S, Blumberg B, Guzelian P S, Evans R M
Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
Genes Dev. 2000 Dec 1;14(23):3014-23. doi: 10.1101/gad.846800.
The cytochrome P450 (CYP) gene products such as CYP3A and CYP2B are essential for the metabolism of steroid hormones and xenochemicals including prescription drugs. Nuclear receptor SXR/PXR (steroid and xenobiotic receptor/pregnenolone X receptor) has been shown both biochemically and genetically to activate CYP3A genes, while similar studies have established constitutive androstane receptor (CAR) as a CYP2B regulator. The response elements in these genes are also distinct, furthering the concept of independent regulation. Unexpectedly, we found that SXR can regulate CYP2B, both in cultured cells and in transgenic mice via adaptive recognition of the phenobarbital response element (PBRE). In a type of functional symmetry, orphan receptor CAR was also found to activate CYP3A through previously defined SXR/PXR response elements. These observations not only provide a rational explanation for the activation of multiple CYP gene classes by certain xenobiotics, but also reveal the existence of a metabolic safety net that confers a second layer of protection to the harmful effects of toxic compounds and at the same time increases the propensity for drug-drug interactions.
细胞色素P450（CYP）基因产物，如CYP3A和CYP2B，对于类固醇激素和包括处方药在内的外源性化学物质的代谢至关重要。核受体SXR/PXR（类固醇和外源性物质受体/孕烯醇酮X受体）已在生化和遗传学方面被证明可激活CYP3A基因，而类似研究已确定组成型雄甾烷受体（CAR）为CYP2B的调节因子。这些基因中的反应元件也各不相同，进一步支持了独立调节的概念。出乎意料的是，我们发现SXR可在培养细胞和转基因小鼠中通过对苯巴比妥反应元件（PBRE）的适应性识别来调节CYP2B。在一种功能对称的情况下，还发现孤儿受体CAR可通过先前定义的SXR/PXR反应元件激活CYP3A。这些观察结果不仅为某些外源性物质激活多种CYP基因类别提供了合理的解释，还揭示了一种代谢安全网的存在，该安全网为有毒化合物的有害影响提供了第二层保护，同时增加了药物相互作用的可能性。
