Protection by superoxide dismutase, catalase, and poly(ADP-ribose) synthetase inhibitors against alloxan- and streptozotocin-induced islet DNA strand breaks and against the inhibition of proinsulin synthesis.
We have shown previously that alloxan and streptozotocin, two major diabetogenic agents, cause DNA strand breaks in rat pancreatic islets and stimulate nuclear poly(ADP-ribose) synthetase, thereby depleting intracellular NAD level and inhibiting proinsulin synthesis (Okamoto, H. (1981) Mol. Cell. Biochem. 37, 43-61; Yamamoto, H., Uchigata, Y., and Okamoto, H. (1981) Nature 294, 284-286). In the present study, superoxide dismutase and catalase, scavengers of radical oxygens, were found to protect against islet DNA strand breaks and inhibition of proinsulin synthesis induced by alloxan. The radical scavengers did not affect islet DNA strand breaks or inhibition of proinsulin synthesis induced by streptozotocin. On the other hand, compounds that inhibit islet nuclear poly(ADP-ribose) synthetase were found to protect against alloxan- as well as streptozotocin-induced inhibition of proinsulin synthesis. The poly(ADP-ribose) synthetase inhibitors were ineffective in protection against DNA strand breaks induced by the agents. These results may provide an important clue for elucidating the prevention of insulin-dependent diabetes as well as for understanding the cause of diabetes.
D000496:Alloxan / Q000494:pharmacology*; D000577:Amides / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002374:Catalase / Q000037:antagonists & inhibitors*; D004261:DNA Replication / Q000187:drug effects*; D005978:Glutathione / Q000494:pharmacology; D066298:In Vitro Techniques; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009244:NAD+ Nucleosidase / Q000037:antagonists & inhibitors*; D009536:Niacinamide / Q000494:pharmacology; D010848:Picolinic Acids / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011384:Proinsulin / Q000235:genetics*; D051381:Rats; D011919:Rats, Inbred Strains; D013311:Streptozocin / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors*; D013806:Theophylline / Q000494:pharmacology
D000577:Amides; D001549:Benzamides; D010848:Picolinic Acids; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009536:Niacinamide; D013311:Streptozocin; D000496:Alloxan; D011384:Proinsulin; D013806:Theophylline; D002374:Catalase; D013482:Superoxide Dismutase; D009244:NAD+ Nucleosidase; D005978:Glutathione; C003142:picolinamide