The gender-dependent difference of liver GSH antioxidant system in mice and its influence on isoline-induced liver injury
The gender-dependent difference of liver GSH antioxidant system in mice and its influence on isoline-induced liver injury
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小鼠肝脏GSH抗氧化系统的性别差异及其对异碱诱导肝损伤的影响
DOI：
10.1016/j.tox.2010.11.010
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发表时间：
2011-02-04
期刊：
影响因子：
4.5
通讯作者：
Wang, Zhengtao
中科院分区：
文献类型：
--
作者：
Liang, Qingning;Sheng, Yuchen;Wang, Zhengtao
细胞内还原型谷胱甘肽（GSH）抗氧化系统是对抗氧化应激所致肝损伤的关键。本研究旨在观察谷胱甘肽抗氧化系统的性别差异及其对肝毒性吡咯里西啶生物碱（HPA）异株碱所致肝损伤的影响。雄性小鼠肝脏谷氨酸-半胱氨酸连接酶（GCL）和谷胱甘肽过氧化物酶（GPx）的活性和蛋白表达均低于雌性小鼠。Isoline是一种天然的HPA，我们进一步的研究表明，与雌性小鼠相比，雄性小鼠表现出更高的血清ALT/AST水平，更少的GSH含量，更低的GCL和GPx活性和蛋白质。N-乙酰-L-半胱氨酸（NAC）是细胞内GSH生物合成的前体物质，可减轻isoline引起的肝损伤。L-丁硫氨酸-（S，R）-亚砜亚胺（BSO）和巯基琥珀酸（MA），GCL和GPx的抑制剂，都增强了isoline诱导的小鼠肝细胞毒性。BSO和MA也增加了其他天然HPAs clivorine和senecionine诱导的细胞毒性。结果表明，雌性小鼠GCL和GPx活性较高，提示其在调节雌性小鼠抗肝毒素性肝损伤中的重要作用。同时，我们的研究结果还首次揭示了HPAs诱导的雌性抗性肝损伤。(C)2010爱思唯尔爱尔兰有限公司版权所有。
Intracellular reduced glutathione (GSH) antioxidant system is crucial for counteracting oxidative stress-induced liver injury. The present study was designed to observe the gender-dependent difference of GSH antioxidant system and its influence on hepatotoxic pyrrolizidine alkaloid (HPA) isoline-induced liver injury. Lower activities and protein expressions of glutamate-cysteine ligase (GCL) and glutathione peroxidase (GPx) were found in male mice livers than in female. Isoline is a natural HPA, our further results showed that male mice demonstrated more higher serum ALT/AST levels, less GSH amounts, lower GCL and GPx activities and proteins induced by isoline as compared to female. N-acetyl-L-cysteine (NAC), which is the precursor of cellular GSH biosynthesis, ameliorated liver injury induced by isoline. L-Buthionine-(S, R)-sulfoximine (BSO) and mercaptosuccinic acid (MA), inhibitors of GCL and GPx, both augmented isoline-induced cytotoxicity in cultured mice hepatocytes. BSO and MA also increased other natural HPAs clivorine and senecionine-induced cytotoxicity. Taken together, our results demonstrated the higher GCL and GPx activities in female mice, which indicated their crucial roles in regulating the resistance of liver injury induced by hepatotoxins in female. Meanwhile, our results also revealed the female-resistant liver injury induced by HPAs for the first time. (C) 2010 Elsevier Ireland Ltd. All rights reserved.