孕烷X受体的研究进展及其在药物代谢中的作用

Progress in research of pregnane X receptor and its effect on drug metabolism

孕烷X受体(pregnane X receptor,PXR)是机体对有毒物质适应性防卫机制的一个重要组成部分,PXR被大量的外源性和内源性化学物质激活,这些物质包括类固醇、抗生素、抗真菌的物质和胆汁酸等。PXR配体结合区域三维结构显示它具有一个特殊球形配体结合腔,这种结构允许PXR与广泛的疏水性化学物质结合。PXR与9-顺式维甲酸受体(9-cisretinoic aid receptor,RXR)以异型二聚体的形式与细胞色素氧化酶P450 3A家族和其他参与药物代谢的Ⅱ相药物代谢酶以及药物转运蛋白的DNA响应元件结合,通过外源物刺激诱导多个基因的表达。分析PXR的结构与功能对药物设计和筛选具有重要的应用价值。

The nuclear pregnane X receptor（PXR） is an important component of the adaptive defense mechanism in the body against toxic substances including foreign chemicals（xenobiotics）.PXR is activated by a large number of endogenous and exogenous chemicals including steroids,antibiotics,antimycotics and bile acids.The three-dimensional structure of the PXR ligand binding domain has been elucidated.This domain has a large and spherical ligand binding cavity that allows it to interact with a wide range of hydrophobic chemicals. PXR binds as a heterodimer with the 9-cis retinoic acid receptor（RXR） to DNA response elements in the regulatory regions of cytochrome P450 3A monooxygenase genes and a number of other phase Ⅱ drug metabolism enzymes,and drug transporter involved in the metabolism,thereby induces the expression of several genes to eliminate of xenobiotics from the body.Understanding the structure and effect of PXR will be useful in the design and screening of drugs.