The gender-dependent difference of liver GSH antioxidant system in mice and its influence on isoline-induced liver injury

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.