Lower susceptibility of female mice to acetaminophen hepatotoxicity: Role of mitochondrial glutathione, oxidant stress and c-jun N-terminal kinase.
Lower susceptibility of female mice to acetaminophen hepatotoxicity: Role of mitochondrial glutathione, oxidant stress and c-jun N-terminal kinase.
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DOI：
10.1016/j.taap.2014.09.002
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发表时间：
2014-11-15
影响因子：
3.8
通讯作者：
Jaeschke, Hartmut
中科院分区：
文献类型：
--
作者：
Du, Kuo;Williams, C. David;McGill, Mitchell R.;Jaeschke, Hartmut
关键词：
对乙酰氨基酚（APAP）过量会导致动物和人类严重的肝毒性。然而，小鼠对APAP过量的易感性的性别差异的潜在机制尚未阐明。在我们的研究中，APAP（300 mg/kg）在雄性小鼠中引起严重的肝损伤，但在雌性小鼠中损伤降低69-77%。APAP的代谢活化没有性别差异，肝脏谷胱甘肽（GSH）在两种性别小鼠中迅速耗尽，而在雌性小鼠中，GSH在线粒体中的恢复在4 h时是2.6倍，在4 h和6 h时在整个肝脏中分别是2.5和3.3倍。GSH的这种更快的恢复与谷氨酸-半胱氨酸连接酶的更大诱导相关，减弱了雌性小鼠的线粒体氧化应激，如6 h时较低的GSSG/GSH比率（雄性为3.8%，雌性为1.4%）和最小的小叶中心硝基酪氨酸染色所示。虽然c-jun N-末端激酶（JNK）活化在APAP后2和4小时相似，但在雌性小鼠中，其在6小时时低3.1倍。然而，雌性小鼠仍然受到JNK抑制剂SP 600125的保护。17β-雌二醇预处理中度降低雄性小鼠的肝损伤和氧化应激，而不影响GSH恢复。结论：雌性小鼠的易感性较低是通过改善活性氧的解毒来实现的，这是由于线粒体GSH水平的加速恢复，这减弱了晚期JNK活化和肝损伤。然而，即使雌性小鼠的损伤减少，仍然依赖于JNK。虽然17β-雌二醇部分保护雄性小鼠，但不影响肝脏GSH恢复。
Acetaminophen (APAP) overdose causes severe hepatotoxicity in animals and humans. However, the mechanisms underlying the gender differences in susceptibility to APAP overdose in mice have not been clarified. In our study, APAP (300 mg/kg) caused severe liver injury in male mice but 69-77% lower injury in females. No gender difference in metabolic activation of APAP was found. Hepatic glutathione (GSH) was rapidly depleted in both genders, while GSH recovery in female mice was 2.6 fold higher in mitochondria at 4h, and 2.5 and 3.3 fold higher in the total liver at 4h and 6h, respectively. This faster recovery of GSH, which correlated with greater induction of glutamate-cysteine ligase, attenuated mitochondrial oxidative stress in female mice, as suggested by a lower GSSG/GSH ratio at 6h (3.8% in males vs. 1.4% in females) and minimal centrilobular nitrotyrosine staining. While c-jun N-terminal kinase (JNK) activation was similar at 2 and 4h post-APAP, it was 3.1 fold lower at 6h in female mice. However, female mice were still protected by the JNK inhibitor SP600125. 17β-Estradiol pretreatment moderately decreased liver injury and oxidative stress in male mice without affecting GSH recovery. Conclusion: The lower susceptibility of female mice is achieved by the improved detoxification of reactive oxygen due to accelerated recovery of mitochondrial GSH levels, which attenuates late JNK activation and liver injury. However, even the reduced injury in female mice was still dependent on JNK. While 17β-estradiol partially protects male mice, it does not affect hepatic GSH recovery.
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DOI：
10.1073/pnas.251194298
发表时间：
2001-11-20
影响因子：
11.1
作者：
Bennett, BL;Sasaki, DT;Anderson, DW
通讯作者：
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影响因子：
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影响因子：
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作者：
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影响因子：
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作者：
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