Patterson Andrew D, Carlson Bradley A, Li Fei, Bonzo Jessica A, Yoo Min-Hyuk, Krausz Kristopher W, Conrad Marcus, Chen Chi, Gonzalez Frank J, Hatfield Dolph L
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, Maryland 20892, United States.
Chem Res Toxicol. 2013 Jul 15;26(7):1088-96. doi: 10.1021/tx4001013. Epub 2013 Jun 7.
The critical importance of glutathione in mitigating the deleterious effects of electrophile generating drugs such as acetaminophen (APAP) is well established. However, the role of other antioxidant systems, such as that provided by thioredoxin, has not been extensively studied. Selenoprotein thioredoxin reductase 1 (Txnrd1) is important for attenuating activation of the apoptosis signaling-regulating kinase 1 (ASK1) and the c-Jun N-terminal kinase (JNK) pathway caused by high doses of APAP. Therefore, a detailed investigation of the role of Txnrd1 in APAP-induced hepatotoxicity was conducted. Liver-specific Txnrd1 knockout mice (Txnrd1(ΔLiv)) were generated and treated with a hepatotoxic dose (400 mg/kg) of APAP for 1 or 6 h. Liver toxicity was assessed by measuring the activities of liver enzymes aspartate aminotransferase and alanine aminotransferase in serum, in addition to histopathological analysis of liver sections and analysis of glutathione levels. At 1 h post-APAP treatment, total and mitochondrial glutathione levels in control and Txnrd1(ΔLiv) mice were similarly depleted. However, at 6 h post-APAP treatment, Txnrd1(ΔLiv) mice were resistant to APAP toxicity as liver enzymes and histology were not significantly different from the corresponding untreated mice. Analyses revealed the compensatory up-regulation of many of the nuclear factor erythroid 2-related factor 2 (NRF2) target genes and proteins in Txnrd1(ΔLiv) mice with and without APAP treatment. Yet, JNK was phosphorylated to a similar extent in APAP-treated control mice. The results suggest that Txnrd1(ΔLiv) mice are primed for xenobiotic detoxication primarily through NRF2 activation.
谷胱甘肽在减轻诸如对乙酰氨基酚（APAP）等产生亲电试剂的药物的有害影响方面的关键重要性已得到充分证实。然而，其他抗氧化系统的作用，如硫氧还蛋白所提供的抗氧化系统，尚未得到广泛研究。硒蛋白硫氧还蛋白还原酶1（Txnrd1）对于减轻高剂量APAP引起的凋亡信号调节激酶1（ASK1）和c-Jun氨基末端激酶（JNK）途径的激活很重要。因此，对Txnrd1在APAP诱导的肝毒性中的作用进行了详细研究。构建了肝脏特异性Txnrd1基因敲除小鼠（Txnrd1(ΔLiv)），并用肝毒性剂量（400 mg/kg）的APAP处理1或6小时。除了对肝脏切片进行组织病理学分析和分析谷胱甘肽水平外，还通过测量血清中天冬氨酸转氨酶和丙氨酸转氨酶的活性来评估肝脏毒性。在APAP处理后1小时，对照小鼠和Txnrd1(ΔLiv)小鼠的总谷胱甘肽和线粒体谷胱甘肽水平同样降低。然而，在APAP处理后6小时，Txnrd1(ΔLiv)小鼠对APAP毒性具有抗性，因为肝脏酶和组织学与相应的未处理小鼠没有显著差异。分析显示，无论是否用APAP处理，Txnrd1(ΔLiv)小鼠中许多核因子红细胞2相关因子2（NRF2）靶基因和蛋白都有代偿性上调。然而，在经APAP处理的对照小鼠中，JNK的磷酸化程度相似。结果表明，Txnrd1(ΔLiv)小鼠主要通过NRF2激活为异源物解毒做好了准备。
