薬物実験糖尿病発症機序の新しい考察 ストレプトゾトシン及びアロキサン糖尿病について
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We propose new hypotheses for the mechanisms of streptozotocin (STZ) and alloxan inducing experimental diabetes in animals. STZ is transported into pancreatic β 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 β cells. Then, XOD-catalyzing reaction is proceeded as proved by increased formation of uric acid and O_2^- radicals are produced, but β 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 O_2^- generation. Consequently, pancreatic β cells are dually suffered from O_2^- 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 β 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 O_2^- radicals formed from alloxan is excluded, because alloxan itself shows a very potent scavenging effect to O_2^- radicals. Therefore alloxan anion radicals seem to be directly related to the incidence of diabetes by alloxan.
- 公益社団法人日本薬学会の論文
- 1992-11-25
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