The MOE Key Laboratory for Standardization of Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, PR China.
Toxicology. 2011 Feb 4;280(1-2):61-9. doi: 10.1016/j.tox.2010.11.010. Epub 2010 Nov 30.
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.
细胞内还原型谷胱甘肽 (GSH) 抗氧化系统对于对抗氧化应激诱导的肝损伤至关重要。本研究旨在观察 GSH 抗氧化系统的性别依赖性差异及其对肝毒性吡咯里西啶生物碱 (HPA) 同系物诱导肝损伤的影响。与雌性相比，雄性小鼠肝脏中的谷氨酸半胱氨酸连接酶 (GCL) 和谷胱甘肽过氧化物酶 (GPx) 的活性和蛋白表达较低。同系物是一种天然 HPA，我们的进一步结果表明，与雌性相比，雄性小鼠的血清 ALT/AST 水平更高，GSH 含量更少，GCL 和 GPx 的活性和蛋白表达更低。N-乙酰-l-半胱氨酸 (NAC) 是细胞内 GSH 生物合成的前体，可改善同系物诱导的肝损伤。GCL 和 GPx 的抑制剂 l-丁硫氨酸-(S,R)-亚砜 (BSO) 和巯基琥珀酸 (MA) 均增强了培养的小鼠肝细胞中同系物诱导的细胞毒性。BSO 和 MA 还增加了其他天然 HPA 克利夫兰菌素和森西菌素诱导的细胞毒性。总之，我们的结果表明雌性小鼠的 GCL 和 GPx 活性更高，这表明它们在调节雌性小鼠肝毒性诱导的肝损伤抵抗力方面发挥着重要作用。同时，我们的结果还首次揭示了 HPA 诱导的雌性肝损伤抵抗性。
