IRON-INDUCED LIPID-PEROXIDATION IN RAT-LIVER IS ACCOMPANIED BY PREFERENTIAL INDUCTION OF GLUTATHIONE-S-TRANSFERASE-8-8 ISOZYME

Since previous studies from this laboratory have suggested that glutat hione S-transferase (GST) 8-8 of rat belongs to a distinct subgroup of GST isozymes which may be involved in the detoxification of the produ cts of lipid peroxidation (Zimniak et al., J. Biol. Chem. 269, 992-100 0, 1994), during the present studies we examined the effect of iron-in duced lipid peroxidation on the expression of GST 8-8 in rat liver. Ra ts treated with 100 mg/kg body wt iron showed a significant increase i n lipid peroxidation in liver. This was accompanied by a concomitant i ncrease in the expression of GST 8-8 in liver as observed in isoelectr ophoretic analysis of rat liver GSTs, and an increase in GST activity toward 4-HNE, a toxic product of lipid peroxidation toward which GST 8 -8 displays high specific activity. Western blot studies using polyclo nal antibodies specifically recognizing GST 8-8 also indicated that, a mong the GST isozymes of rat liver, GST 8-8 was preferentially induced upon iron treatment. These findings were further confirmed by purifyi ng and quantitating GST 8-8 protein from the controls and iron-treated rats. Significant differences in the specific activities of GST 8-8 p urified from the controls and iron-treated rats were observed, indicat ing that more than one GST isozyme related to GST 8-8 may be present i n rat liver. This observation is consistent with the observed heteroge neity in mouse mGSTA4-4 which is an ortholog of rat GST 8-8. Iron trea tment also caused significant increase in GSH levels probably because of de novo synthesis as indicated by an increase in gamma-glutamyl cys teine synthetase activity. The results of these studies suggest that G ST 8-8, and possibly other related GST isozymes, may play an important role in defense mechanisms against lipid peroxidation. (C) 1995 Acade mic Press, Inc.