ASSOCIATION OF GLUTATHIONE-S-TRANSFERASE ISOZYME-SPECIFIC INDUCTION AND LIPID-PEROXIDATION IN 2 INBRED STRAINS OF MICE SUBJECTED TO CHRONICDIETARY IRON OVERLOAD

The alpha-class glutathione S-transferases are proposed to play a prom inent role in catalyzing the conjugation of glutathione with electroph ilic aldehydic products of lipid peroxidation. The effect of iron-indu ced lipid peroxidation on induction of glutathione S-transferase (GST) isozymes Al and A4 in the livers of male C57/BL6Ibg and DBA/J2Ibg mic e was studied. C57 and DBA mice were fed for 4 months on a diet supple mented with iron as ferrocene and then were assessed for liver injury, hepatic iron loading, indices of lipid peroxidation, GST activity, an d induction of GST isozymes Al and A4, Iron-treated animals displayed a loss in body weight from pair-fed controls and had large increases i n 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 onl y in C57 mice, but hepatic concentrations of reduced glutathione (GSH) were significantly increased in both inbred strains. Total GST activi ty toward 1-chloro-2,4-dinitrobenzene was significantly increased in C 57 mice but not in DBA. Western blot studies using polyclonal antibodi es specific for GST Al 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 i n lipid hydroperoxides, hepatic GSH, GST activity, and GST Al and A4 p rotein strongly support the hypothesis that induction of GST Al and A4 represents an important protective event in the detoxification of ele ctrophilic products of lipid peroxidation. (C) 1998 Academic Press.