Streptozotocin (STZ) is believed to induce pancreatic cell death in mice by depleting the cell of NAD+NADH. The drug is known to cause a greater depletion of cell NAD+NADH in C57bl/6J mice than in Balb/c mice. To investigate the basis for this strain difference, we compared the effects of streptozotocin on poly(ADP-ribose)-polymerase (PARP) activation -the major site of NAD consumption, and on mitochondrial activity -the major site of NAD production.A significant strain difference was demonstrated in STZ-induced PARP activation (fmol NAD incorporated/min/ µg DNA ...: Balb/c control 2·28 0·14, Balb STZ 3·11 0·25; C57bl/6J control 2·57 0·29, C57bl/6J STZ 4·17 0·24). In comparison, no strain difference could be demonstrated in hydrogen-peroxide-induced PARP activation. No strain differences could be detected in the activity of STZ-treated islet mitochondria as measured by determining ATP production (pmol/ µg protein/h ...: Balb/c control 0·20 0·02, Balb/c STZ 0·15 0·02; C57bl/6J control 0·23 0·03, C57bl/6J STZ 0·15 0·02) or by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) dye reduction (change in optical density/mg protein ...: Balb/c control 10·19 0·62, Balb/c STZ 6·01 1·17; C57bl/6J control 6·15 0·98, C57bl/6J STZ 5·81 0·96).The strain difference in STZ-induced NAD depletion appears to be due to a difference in NAD consumption and not a difference in a mitochondrial process involved in replacing decreasing NAD concentrations. It is unlikely that a strain difference in the enzymic activity of PARP is responsible for strain differences in the effects of STZ, as no strain differences in hydrogen-peroxide-induced PARP activation could be detected. Thus the greater PARP activation, NAD depletion and cell death observed in C57bl/6J islets may be due to greater levels of DNA damage or differences in the DNA excision repair processes.
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