Association of glutathione S-transferase isozyme-specific induction and lipid peroxidation in two inbred strains of mice subjected to chronic dietary iron overload

The alpha-class glutathione S-transferases are proposed to play a prominent role in catalyzing the conjugation of glutathione with electrophilic aldehydic products of lipid peroxidation. The effect of iron-induced lipid peroxidation on induction of glutathione S-transferase (GST) isozymes A1 and A4 in the livers of male C57/BL6Ibg and DBA/J2Ibg mice was studied. C57 and DBA mice were fed for 4 months on a diet supplemented with iron as ferrocene and then were assessed for liver injury, hepatic iron loading, indices of lipid peroxidation, GST activity, and induction of GST isozymes A1 and A4. Iron-treated animals displayed a loss in body weight from pair-fed controls and had large increases in hepatic non-heme iron with concomitant liver injury, as measured by serum alanine aminotransferase. Hepatic lipid hydroperoxides, a direct measure of oxidized membrane lipids, were significantly increased only in C57 mice, but hepatic concentrations of reduced glutathione (GSH) were significantly increased in both inbred strains. Total GST activity toward 1-chloro-2,4-dinitrobenzene was significantly increased in C57 mice but not in DBA. Western blot studies using polyclonal antibodies specific for GST A1 and A4 revealed significant increases of 1.5-2.0-fold in these GST isoforms in both inbred strains. These results in a unique murine model for hepatic iron overload further support recent in vivo studies (Khan et al., Toxicol. Appl. Pharmacol., 131, 63-72, 1995) that have associated induction of GST A4 with protection against oxidative stress-induced lipid peroxidation. The observed increases in lipid hydroperoxides, hepatic GSH, GST activity, and GST A1 and A4 protein strongly support the hypothesis that induction of GST A1 and A4 represents an important protective event in the detoxification of electrophilic products of lipid peroxidation.