Regulation of a xenobiotic sulfonation cascade by nuclear pregnane X receptor (PXR)
Regulation of a xenobiotic sulfonation cascade by nuclear pregnane X receptor (PXR)
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DOI：
10.1073/pnas.212494599
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发表时间：
2002-10-15
影响因子：
11.1
通讯作者：
Evans, RM
中科院分区：
文献类型：
--
作者：
Sonoda, J;Xie, W;Evans, RM
核受体PXR（胆烷X受体）通过诱导羟基化细胞色素P450酶CYP 3A的表达和促进解毒来保护身体免受二级胆汁酸如石胆酸（LCA）的肝毒性。我们发现PXR的激活也增加了11相缀合酶脱氢表雄酮磺基转移酶（STD）的活性和基因表达，该酶已知可硫酸化LCA以促进其消除。这种激活是直接的，并且似乎延伸到其他异生素磺基转移酶以及3 '-磷酸腺苷5'-磷酸硫酸合成酶2（PAPSS 2），该酶产生用于反应的供体辅因子。由于硫酸化在许多外源性物质、处方药和毒素的代谢中起着重要作用，我们建议PXR作为I期和II期反应的主要调节剂，以促进快速有效的解毒和消除外来化学物质。
The nuclear receptor PXR (pregnane X receptor) protects the body from hepatotoxicity of secondary bile acids such as lithocholic acid (LCA) by inducing expression of the hydroxylating cytochrome P450 enzyme CYP3A and promoting detoxification. We found that activation of PXR also increases the activity and gene expression of the phase 11 conjugating enzyme dehydroepiandrosterone sulfotransferase (STD) known to sulfate LCA to facilitate its elimination. This activation is direct and appears to extend to other xenobiotic sulfotransferases as well as to 3'-phosphoadenosine 5'-phosphosulfate synthetase 2 (PAPSS2), an enzyme that generates the donor cofactor for the reaction. Because sulfation plays an important role in the metabolism of many xenobiotics, prescription drugs, and toxins, we propose that PXR serves as a master regulator of the phase I and II responses to facilitate rapid and efficient detoxification and elimination of foreign chemicals.