Orphan nuclear receptor pregnane X receptor sensitizes oxidative stress responses in transgenic mice and cancerous cells

被引:85
作者
Gong, HB
Singh, SV
Singh, SP
Mu, Y
Lee, JH
Saini, SPS
Toma, D
Ren, SR
Kagan, VE
Day, BW
Zimniak, P
Xie, W
机构
[1] Univ Pittsburgh, Ctr Pharmacogenet, Pittsburgh, PA 15261 USA
[2] Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA
[3] Univ Pittsburgh, Dept Pharmacol, Pittsburgh, PA 15261 USA
[4] Univ Pittsburgh, Inst Canc, Dept Environm & Occupat Hlth, Pittsburgh, PA USA
[5] Univ Pittsburgh, Dept Chem, Pittsburgh, PA 15260 USA
[6] Univ Arkansas Med Sci, Dept Pharmacol & Toxicol, Little Rock, AR 72205 USA
关键词
D O I
10.1210/me.2005-0205
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
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页码:279 / 290
页数:12
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