Effect of Streptozotocin on Red-blood-cell-reduced Glutathione: Modification by Glucose, Nicotinamide, and Epinephrine

Abstract

Previous studies had shown that administration of streptozotocin to rats produces both diabetes and hemolysis and that both could be ameliorated by prior injections of diazoxide. Thus, it appeared pertinent to define the effect of streptozotocin on the red cell. In the present studies, streptozotocin administered in vivo to rats produced a rapid fall in red-cell-reduced glutathione. This effect was duplicated in vitro in incubated human red cells. Furthermore, it was demonstrated that glucose loading prior to bleeding modified the in-vitro red-cell GSH response to streptozotocin and that preincubation of red cells from fasted individuals with glucose, nicotinamide, and epinephrine (but not nicotinic acid) protected against the subsequent effect of streptozotocin on RBC GSH. The pattern of the RBC GSH response under each of these conditions is that which occurs in response to challenge with an oxidant, that is, with appropriate protection, oxidation stress produces an acute rise rather than falll in gsh. further, when glucose was present through both preincubation and test periods (i.e., in presence of streptozotocin) a third pattern of GSH response was observed--no change. The data are compatible with the postulate that the cytotoxic action of streptozotocin is dependent, in part, on an oxidant effect, and that glucose may protect through at least two mechanisms, that adrenergic stimulation can enhance protective mechanisms against redox insults and so contribute to maintenance of cell viability.

Effect of streptozotocin on erythrocyte and retinal superoxide dismutase

“…In view of our results and those of Slonim et aI. [6], some enzyme abnormalities observed in such animals may be due to direct drug effects rather than a consequence of the diabetic state.…”

“…Streptozotocin reduces islet NAD content in vivo [4] and in vitro [5]. Likewise the reduced glutathione of red blood cells is decreased [6]. Glucose, nicotinamide and epinephrine were found to protect against the latter effect.…”

“…Glucose, nicotinamide and epinephrine were found to protect against the latter effect. These results were interpreted to mean that streptozotocin exerts its cytotoxic effects through the oxidation of glutathione [6].…”

Modification of chemically induced diabetes in rats by vitamin E. Supplementation minimizes and depletion enhances development of diabetes.

“…Schein and co-workers (6) have suggested that alkylation of DNA is the principal mode of streptozotocin's antileukemic action, while depression of NAD is responsible for its diabetogenic effect. We have recently demonstrated that streptozotocin, as well as alloxan, induces a change in the cellular redox state, causing a fall in blood GSH in rats (7), and a fall in GSH and rise in oxidized glutathione (GSSG) in rat islets and erythrocytes in vitro (8). These findings suggest that streptozotocin may also act as an oxidant, and this action may be associated with its diabetogenic effect.…”

Protection against streptozotocin-induced diabetes by superoxide dismutase

“…While its precise mode of action is unknown, it appears to alter the redox state of the affected cells. Specifically, streptozotocin has been shown to decrease pyridine nucleotide levels in isolated islets [3,4], to decrease levels of reduced glutathione in erythrocytes [5], and to deplete erythrocytic and retinal levels of superoxide dismutase (Superoxide oxidoreductase erythrocuprin EC. 1:15.1.1 bovine) [6].…”