[New hypotheses for the mechanisms of streptozotocin and alloxan inducing diabetes mellitus].
We propose new hypotheses for the mechanisms of streptozotocin (STZ) and alloxan inducing experimental diabetes in animals. STZ is transported into pancreatic beta cells through glucose transporter in the cell membranes and attacks mitochondria. Mitochondrial ATP generation is inhibited and the resulting high concentration of intracellular ADP causes its degradation providing hypoxanthine, a substrate of xanthine oxidase (XOD) whose activity is intrinsically very high in beta cells. Then, XOD-catalyzing reaction is proceeded as proved by increased formation of uric acid and O2- radicals are produced, but beta cells are inefficient to scavenge these radicals because of their extremely low activity of superoxide dismutase. On the other hand, STZ directly activates XOD and enhances O2- generation. Consequently, pancreatic beta cells are dually suffered from O2- radicals or probably hydroxyl radicals derived from the former when exposed to STZ. Allopurinol, an inhibitor of XOD, can protect animals from the diabetogenic effect of STZ. In pancreatic beta cells, alloxan anion radicals are generated from alloxan probably mediated by the action of microsomal cytochrome P-450 system. These radicals have long half-life and directly damage DNA in vitro. The widely accepted hypothesis that the cause of alloxan-induced diabetes is attributable to O2- radicals formed from alloxan is excluded, because alloxan itself shows a very potent scavenging effect to O2- radicals. Therefore alloxan anion radicals seem to be directly related to the incidence of diabetes by alloxan.
Kawada
J
J
Faculty of Pharmaceutical Sciences, University of Tokushima, Japan.
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000496:Alloxan; D000818:Animals; D004249:DNA Damage; D003921:Diabetes Mellitus, Experimental / Q000209:etiology / Q000378:metabolism*; D005609:Free Radicals; D019271:Hypoxanthine; D007042:Hypoxanthines / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013311:Streptozocin; D014527:Uric Acid / Q000378:metabolism; D014969:Xanthine Oxidase / Q000378:metabolism
D005609:Free Radicals; D007042:Hypoxanthines; D017382:Reactive Oxygen Species; D014527:Uric Acid; D019271:Hypoxanthine; D013311:Streptozocin; D000244:Adenosine Diphosphate; D000496:Alloxan; D000255:Adenosine Triphosphate; D014969:Xanthine Oxidase