Orphan nuclear receptor pregnane X receptor sensitizes oxidative stress responses in transgenic mice and cancerous cells
Orphan nuclear receptor pregnane X receptor sensitizes oxidative stress responses in transgenic mice and cancerous cells
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DOI：
10.1210/me.2005-0205
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发表时间：
2006-02-01
影响因子：
--
通讯作者：
Xie, W
中科院分区：
文献类型：
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作者：
Gong, HB;Singh, SV;Xie, W
有效处理氧化应激对生物体的生存至关重要。孤儿核受体孕烷X受体(PXR)通过调节I期和II期药物代谢/解毒酶和转运蛋白，在异种生物解毒中发挥重要作用。在这项研究中，我们意外地发现，在转基因雌性小鼠中表达激活的人PXR导致了对百草枯的高度敏感性，百草枯是一种氧化性异源毒物。用小鼠PXR激动剂孕烯醇酮-16α-碳腈治疗的野生型小鼠对百草枯的敏感性也有所提高。PXR诱导的百草枯敏感性与超氧化物歧化酶和过氧化氢酶的活性降低有关，这两种酶分别清除超氧化物歧化酶和过氧化氢。矛盾的是，谷胱甘肽S转移酶的普遍表达和活性也在转基因小鼠中被诱导出来，谷胱甘肽转移酶是一种解毒亲电和细胞毒性底物的II相酶家族。PXR以同工酶、组织特异性和性别特异性的方式调节谷胱甘肽S转移酶的表达，这种调节不依赖于核因子-红系2 P45相关因子2/凯氏样Ech相关蛋白1途径。在细胞培养中，活化的人PXR的表达使结肠癌和肝细胞对百草枯的细胞毒性作用敏感，这与活性氧物种的产生增加有关。目前的研究揭示了PXR在哺乳动物氧化应激反应中的一个新功能，这一调控途径可能通过使正常组织和癌症组织对氧化细胞损伤敏感而参与癌症的发生。
Efficient handling of oxidative stress is critical for the survival of organisms. The orphan nuclear receptor pregnane X receptor (PXR) is important in xenobiotic detoxification through its regulation of phase I and phase II drug-metabolizing/detoxifying enzymes and transporters. In this study we unexpectedly found that the expression of an activated human PXR in transgenic female mice resulted in a heightened sensitivity to paraquat, an oxidative xenobiotic toxicant. Heightened paraquat sensitivity was also seen in wild-type mice treated with the mouse PXR agonist pregnenolone-16 alpha-carbonitrile. The PXR-induced paraquat sensitivity was associated with decreased activities of superoxide dismutase and catalase, enzymes that scavenge superoxide and hydrogen peroxide, respectively. Paradoxically, the general expression and activity of glutathione S-transferases, a family of phase II enzymes that detoxify electrophilic and cytotoxic substrates, was also induced in the transgenic mice. PXR regulates glutathione S-transferase expression in an isozyme-, tissue-, and sex- specific manner, and this regulation is independent of the nuclear factor-erythroid 2 p45-related factor 2/Kelch-like Ech-associated protein 1 pathway. In cell cultures, expression of activated human PXR sensitizes the cancerous colon and liver cells to the cytotoxic effect of paraquat, which is associated with an increased production of the reactive oxygen species. The current study reveals a novel function of PXR in the mammalian oxidative stress response, and this regulatory pathway may be implicated in carcinogenesis by sensitizing normal and cancerous tissues to oxidative cellular damage.