Szkudelski T
Department of Animal Physiology and Biochemistry, University of Agriculture, Poznan, Poland.
Physiol Res. 2001;50(6):537-46.
Alloxan and streptozotocin are widely used to induce experimental diabetes in animals. The mechanism of their action in B cells of the pancreas has been intensively investigated and now is quite well understood. The cytotoxic action of both these diabetogenic agents is mediated by reactive oxygen species, however, the source of their generation is different in the case of alloxan and streptozotocin. Alloxan and the product of its reduction, dialuric acid, establish a redox cycle with the formation of superoxide radicals. These radicals undergo dismutation to hydrogen peroxide. Thereafter highly reactive hydroxyl radicals are formed by the Fenton reaction. The action of reactive oxygen species with a simultaneous massive increase in cytosolic calcium concentration causes rapid destruction of B cells. Streptozotocin enters the B cell via a glucose transporter (GLUT2) and causes alkylation of DNA. DNA damage induces activation of poly ADP-ribosylation, a process that is more important for the diabetogenicity of streptozotocin than DNA damage itself. Poly ADP-ribosylation leads to depletion of cellular NAD+ and ATP. Enhanced ATP dephosphorylation after streptozotocin treatment supplies a substrate for xanthine oxidase resulting in the formation of superoxide radicals. Consequently, hydrogen peroxide and hydroxyl radicals are also generated. Furthermore, streptozotocin liberates toxic amounts of nitric oxide that inhibits aconitase activity and participates in DNA damage. As a result of the streptozotocin action, B cells undergo the destruction by necrosis.
四氧嘧啶和链脲佐菌素被广泛用于诱导动物实验性糖尿病。它们在胰腺β细胞中的作用机制已得到深入研究，目前已相当清楚。这两种致糖尿病药物的细胞毒性作用均由活性氧介导，然而，在四氧嘧啶和链脲佐菌素的情况下，其产生的来源不同。四氧嘧啶及其还原产物二羟脲酸形成一个氧化还原循环，生成超氧自由基。这些自由基歧化生成过氧化氢。此后，通过芬顿反应形成高活性的羟基自由基。活性氧的作用与胞质钙浓度同时大幅增加，导致β细胞迅速破坏。链脲佐菌素通过葡萄糖转运蛋白（GLUT2）进入β细胞，导致DNA烷基化。DNA损伤诱导多聚ADP-核糖基化的激活，这一过程对链脲佐菌素的致糖尿病性比DNA损伤本身更重要。多聚ADP-核糖基化导致细胞内NAD+和ATP耗竭。链脲佐菌素处理后增强的ATP去磷酸化为黄嘌呤氧化酶提供底物，导致超氧自由基的形成。因此，也会产生过氧化氢和羟基自由基。此外，链脲佐菌素释放出有毒量的一氧化氮，抑制乌头酸酶活性并参与DNA损伤。由于链脲佐菌素的作用，β细胞通过坏死而被破坏。
