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Importance of the concentration of ATP in rat pancreatic beta cells in the mechanism of streptozotocin-induced cytotoxicity.

The effects of streptozotocin (STZ) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) on monolayer cultures of rat pancreatic beta cells were compared. The intracellular NAD concentration was markedly decreased by both 2 mmol STZ/l and 13.6 mumol MNNG/l, but insulin secretion was decreased significantly only by STZ. The intracellular ATP level decreased rapidly and in a time-dependent manner with STZ, but decreased less on treatment with MNNG: 80% decrease with STZ but only 35% decrease with MNNG in 12 h in the cells exposed to the chemicals for 1 h and then washed thoroughly. STZ decreased oxygen consumption of rat liver mitochondria in a time- and dose-dependent manner and enhanced the generation of hydroxyl radicals (DMPO-adducts). This enhancement was doubled on the addition of succinate as a substrate. Mitochondrial ATP production was also decreased significantly by STZ, but not by MNNG. Thus the marked depletion of intracellular ATP in beta cells by STZ seems to be due mainly to a direct effect on mitochondrial production. From these results, we suggest that the cytotoxic effect of STZ in pancreatic beta cells is due to a reduction in the intracellular level of ATP, rather than of NAD.