Recent findings suggest a functional interaction of the drug resistance enzyme glutathione S-transferase P (GSTP) with the transcription factor Nrf2, a master regulator of the adaptive stress response to cellular electrophiles. The effect of this interaction on the metabolism and redox of cellular thiols was investigated in this study during the exposure to alkylating Se-compounds in murine embryonic fibroblasts (MEFs). GSTP1-1 gene ablation was confirmed to upregulate Nrf2 activity and to increase Cys uptake and the de novo biosynthesis of reduced glutathione (GSH) that was readily released in the extracellular medium together with other cellular thiols. This latter response was associated with a higher expression of the membrane transporter MRP1 and was markedly stimulated by the treatment with alkylating Se-compounds together with protein S-glutathionylation that was observed to be under the influence of GSTP expression. The response of cellular thiols to Se-compounds was not altered by the transient (SiRNA-induced) or stable inactivation of NRF2 in GSTP competent or hGSTP1 transfected cells, while defects of GSH biosynthesis, efflux, and redox were observed after NRF2 silencing in GSTP^−/− MEFs. In conclusion, GSTP is confirmed to functionally interact with Nrf2 and to have a prominent position in the pecking order of factors that control both the Nrf2-dependent and independent response of cellular thiols to alkylating agents.

中文翻译：

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谷胱甘肽S-转移酶P影响细胞硫醇对硒化合物的Nrf2依赖性反应。

最近的发现表明，抗药性酶谷胱甘肽S-转移酶P（GSTP）与转录因子Nrf2的功能相互作用，转录因子Nrf2是对细胞亲电子试剂的适应性应激反应的主要调节剂。在鼠胚胎成纤维细胞（MEFs）的烷基化硒化合物暴露过程中，研究了这种相互作用对细胞硫醇代谢和氧化还原的影响。GSTP1-1基因消融被证实可以上调Nrf2活性，并增加Cys的摄取和从头开始的还原型谷胱甘肽（GSH）的生物合成，该谷胱甘肽与其他细胞硫醇一起容易释放在细胞外培养基中。后者的反应与膜转运蛋白MRP1的较高表达有关，并且被烷基化硒化合物和蛋白S-谷胱甘肽化的处理显着刺激，据观察，其受GSTP表达的影响。细胞硫醇的为Se化合物的响应没有被瞬时改变（siRNA诱导）或稳定灭活NRF2在GSTP主管或hGSTP1转染的细胞，而后观察GSH合成，外排，和氧化还原的缺陷GSTP ^-/- MEF中的NRF2沉默。总之，证实GSTP与Nrf2在功能上相互作用，并且在控制细胞硫醇对烷基化剂的Nrf2依赖性和非依赖性反应的因素的啄食顺序中处于显着位置。