Activation of CAR and PXR by Dietary, Environmental and Occupational Chemicals Alters Drug Metabolism, Intermediary Metabolism, and Cell Proliferation.
Activation of CAR and PXR by Dietary, Environmental and Occupational Chemicals Alters Drug Metabolism, Intermediary Metabolism, and Cell Proliferation.
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DOI：
10.2174/187569209788654005
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发表时间：
2009-06-01
影响因子：
--
通讯作者：
Baldwin WS
中科院分区：
文献类型：
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作者：
Hernandez JP;Mota LC;Baldwin WS
组成型雄甾烷受体（CAR）和孕烷×受体（PXR）被多种内源性和外源性配体激活，例如类固醇激素、胆汁酸、药物以及环境、饮食和职业化学品。反过来，它们诱导 I-III 相解毒酶和转运蛋白，帮助消除这些化学物质。由于许多激活 CAR 和 PXR 的化学物质与环境相关（饮食和人为），因此研究需要确定这些化学物质或这些化学物质的混合物是否可能增加对不良药物相互作用的敏感性。此外，CAR和PXR还参与肝脏增殖、中间代谢和防止胆汁淤积。因此，CAR 和 PXR 的激活可能通过对代谢和细胞增殖的生理影响对个性化医疗产生广泛的影响。 some beneficial and others adverse.识别激活这些混杂核受体的化学物质并了解这些化学物质如何协同作用将有助于我们预测药物不良反应（ADR）、预测胆汁淤积和脂肪变性以及调节中间代谢。本综述总结了 CAR 和 PXR 的现有数据，包括激活这些受体的环境化学物质、它们控制的基因，以及受到干扰或依赖于 CAR 和 PXR 作用的生理过程。这些知识为辨别这些关键核受体调节的下游生物途径的个体间差异奠定了必要的基础。
The constitutive androstane receptor (CAR) and the pregnane × receptor (PXR) are activated by a variety of endogenous and exogenous ligands, such as steroid hormones, bile acids, pharmaceuticals, and environmental, dietary, and occupational chemicals. In turn, they induce phase I–III detoxification enzymes and transporters that help eliminate these chemicals. Because many of the chemicals that activate CAR and PXR are environmentally-relevant (dietary and anthropogenic), studies need to address whether these chemicals or mixtures of these chemicals may increase the susceptibility to adverse drug interactions. In addition, CAR and PXR are involved in hepatic proliferation, intermediary metabolism, and protection from cholestasis. Therefore, activation of CAR and PXR may have a wide variety of implications for personalized medicine through physiological effects on metabolism and cell proliferation; some beneficial and others adverse. Identifying the chemicals that activate these promiscuous nuclear receptors and understanding how these chemicals may act in concert will help us predict adverse drug reactions (ADRs), predict cholestasis and steatosis, and regulate intermediary metabolism. This review summarizes the available data on CAR and PXR, including the environmental chemicals that activate these receptors, the genes they control, and the physiological processes that are perturbed or depend on CAR and PXR action. This knowledge contributes to a foundation that will be necessary to discern interindividual differences in the downstream biological pathways regulated by these key nuclear receptors.