Phthalate induction of CYP3A4 is dependent on glucocorticoid regulation of PXR expression
Phthalate induction of CYP3A4 is dependent on glucocorticoid regulation of PXR expression
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DOI：
10.1093/toxsci/kfn047
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发表时间：
2008-06-01
影响因子：
3.8
通讯作者：
Wallace, Andrew D.
中科院分区：
文献类型：
--
作者：
Cooper, Beth W.;Cho, Taehyeon M.;Wallace, Andrew D.
细胞色素P450 3A4 （CYP3A4）负责超过60%的所有药物的氧化代谢。CYP3A4可被激活妊娠X受体（PXR）的外源性药物诱导，并且CYP3A4活性的增强与不良药物相互作用有关。最近的证据表明，广泛使用的增塑剂邻苯二甲酸二乙己酯（DEHP）及其主要代谢物邻苯二甲酸单2-乙基己酯（MEHP）可能作为PXR的激动剂。医院病人是唯一暴露于高水平DEHP以及被给予糖皮质激素。糖皮质激素在糖皮质激素受体（GR）介导的机制中积极调节PXR的表达。我们认为邻苯二甲酸盐诱导CYP3A4的程度取决于PXR的表达，并且在糖皮质激素存在时可能明显更高。DEHP和MEHP以剂量依赖性方式诱导pxr介导的CYP3A4启动子转录。共暴露于邻苯二甲酸盐和地塞米松（Dex）导致CYP3A4启动子活性增强；此外，这种诱导作用被GR拮抗剂RU486和GR小干扰核糖核酸所消除。Dex诱导PXR蛋白在人肝细胞和肝源性大鼠细胞系中的表达。Dex和DEHP共给药可诱导人肝细胞中CYP3A4蛋白的表达。最后，Dex和邻苯二甲酸盐共处理的人肝细胞中6 -羟睾酮的形成增强，证实了CYP3A4酶的诱导作用。同时暴露于糖皮质激素和邻苯二甲酸盐导致CYP3A4代谢活性增强，可能在药物制剂的疗效改变中起作用。了解糖皮质激素对PXR的调节作用，作为外源性药物诱导CYP3A4程度的关键决定因素，可能有助于了解敏感人群的药物不良反应。
Cytochrome P450 3A4 (CYP3A4) is responsible for oxidative metabolism of more than 60% of all pharmaceuticals. CYP3A4 is inducible by xenobiotics that activate pregnane X receptor (PXR), and enhanced CYP3A4 activity has been implicated in adverse drug interactions. Recent evidence suggest that the widely used plasticizer, di-2-ethylhexyl phthalate (DEHP), and its primary metabolite mono-2-ethylhexyl phthalate (MEHP) may act as agonists for PXR. Hospital patients are uniquely exposed to high levels of DEHP as well as being administered glucocorticoids. Glucocorticoids positively regulate PXR expression in a glucocorticoid receptor (GR)-mediated mechanism. We suggest that the magnitude of CYP3A4 induction by phthalates is dependent on the expression of PXR and may be significantly higher in the presence of glucocorticoids. DEHP and MEHP induced PXR-mediated transcription of the CYP3A4 promoter in a dose-dependent fashion. Coexposure to phthalates and dexamethasone (Dex) resulted in enhanced CYP3A4 promoter activity; furthermore, this induction was abrogated by both the GR antagonist RU486 and GR small interfering ribonucleic acid. Dex induced PXR protein expression in human hepatocytes and a liver-derived rat cell line. CYP3A4 protein was highly induced by Dex and DEHP coadministration in human hepatocyte cultures. Finally, enhanced 6 beta-hydroxytestosterone formation in Dex and phthalate cotreated human hepatocytes confirmed CYP3A4 enzyme induction. Concomitant exposure to glucocorticoids and phthalates resulting in enhanced metabolic activity of CYP3A4 may play a role in altered efficacy of pharmaceutical agents. Understanding the role of glucocorticoid regulation of PXR as a key determinant in the magnitude of CYP3A4 induction by xenobiotics may provide insight into adverse drug effects in a sensitive population.