The Inhibition of Islet Superoxide Dismutase by Diabetogenic Drugs

Abstract

The enzyme superoxide dismutase (SOD) is a scavenger of superoxide radicals and protects the integrity of cell membranes. We previously reported that streptozotocin inhibits the SOD activity of erythrocytes and retinae in vivo and in vitro. We now report that the three major diabetogenic drugs, i.e., alloxan, streptozotocin, and Vacor (in order of increasing potency), interact with erythrocyte Cu-Zn SOD in vitro. Maximum inhibition of erythrocyte SOD of man, dog, rat, and cow is 40% and is achieved within 10 min. At submaximal doses the effect of the three drugs is additive. Inhibition induced by streptozotocin, but not by the other two agents, is reversible by dialysis. Alloxan (80 mg/kg), like streptozotocin, also inhibits erythrocyte SOD activity when injected i.v. into rats. Glucose or 3- o-methylglucose does not prevent SOD inhibition by alloxan or streptozotocin in vitro. Injection of glucose before alloxan prevents the development of diabetes, but does not prevent alloxan-lnduced inhibition of erythrocyte SOD. SOD is present in the islets of Langerhans of rats and dogs, as demonstrated by biochemical assay of isolated islets and by immunofluorescent staining of frozen pancreases. The specific activity of SOD in the islets exceeds that of the exocrine pancreas more than 100-fold. The islet SOD is of the Cu-Zn type, since it is inhibited by KCN, and not by chloroformethanol. The mobility of the islet enzyme on polyacrylamlde disc gel electrophoresis is different from that of erythrocyte SOD. Streptozotocin, alloxan, and Vacor Inhibit the activity of islet SOD in vitro; the rate and magnitude of inhibition is the same as that observed with erythrocyte SOD. The Mn SOD of liver mitochondria is not affected by the diabetogenic drugs. It is suggested that the inhibitory effect of the diabeto- genie drugs on islet cell SOD may contribute to their cytotoxicity, and that changes in the amount or activity of this protective enzyme in β-cells may play a role in determining their vulnerability to noxious agents.