The effect of 3-methyladenine DNA glycosylase-mediated DNA repair on the induction of toxicity and diabetes by the β-cell toxicant streptozotocin
The effect of 3-methyladenine DNA glycosylase-mediated DNA repair on the induction of toxicity and diabetes by the β-cell toxicant streptozotocin
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DOI：
10.1093/toxsci/kfl164
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发表时间：
2007-02-01
影响因子：
3.8
通讯作者：
Gold, Barry
中科院分区：
文献类型：
--
作者：
Burns, Nicole;Gold, Barry
人类I型糖尿病是由胰腺β细胞的自体免疫破坏引起的，通常出现在儿童时期。遗传易感性是一个潜在的原因，但环境因素，即毒素和病毒，被认为是初始因素。在环境或生理事件的反应中，β细胞死亡的潜在作用已被研究为糖尿病发病的关键事件。一种经过充分研究的1型糖尿病啮齿动物模型使用链脲佐菌素（STZ）诱导β细胞死亡。STZ是一种选择性的β细胞基因毒物，当单次高剂量给药时，它通过产生DNA加合物（包括n3 -甲基腺嘌呤和o -6-甲基鸟嘌呤加合物）诱导糖尿病的快速发作，随后p细胞坏死死亡。在目前的工作中，我们扩展了先前的研究，报道了n3 -甲基腺嘌呤加合物，3-甲基腺嘌呤DNA糖基化酶（烷基腺嘌呤DNA糖基化酶[Aag]）修复缺陷的小鼠对STZ的直接细胞毒性作用具有抗性，但后来发展为自身免疫性糖尿病（J. W. Cardinal et al., 2001, Mol.Cell.Biol）。231年,5605 - 5613)。我们发现，单次高剂量STZ治疗的Aag（-/-）小鼠可防止广泛的β细胞坏死和糖尿病。然而，在Aag(-/-) stz处理的小鼠中观察到中等水平的β细胞凋亡。虽然小鼠在研究期间（注射STZ后14个月）出现葡萄糖受损，但没有发生明显的糖尿病。我们的结论是，在Aag（-/-）小鼠对β细胞凋亡的反应中，自身免疫反应没有启动。此外，在Aag /-处理的小鼠中没有观察到肿瘤的发展，这表明在基因组中积累的n3 -甲基腺嘌呤加合物可能不会在β细胞中产生促生作用。
Type I diabetes in humans arises from the autoinumme destruction of pancreatic beta-cells and typically presents in childhood. Genetic susceptibility is an underlying cause, but environmental agents, that is, toxins and viruses, are postulated to be initiating factors. The underlying role of beta-cell death in response to environmental or physiologic events has been investigated as a critical event in diabetes onset. A well-studied rodent model for type I diabetes utilizes streptozotocin (STZ) to induce beta-cell death. STZ is a selective beta-cell genotoxicant, and when administered in a single high dose it induces rapid onset of diabetes by generating DNA adducts, including N3-methyladenine and O-6-methylguanine adducts, and subsequently P-cell death by necrosis. In the present work, we have extended previous studies in which mice deficient in the repair of N3-methyladenine adducts, 3-methyladenine DNA glycosylase (alkyladenine DNA glycosylase [Aag]) null mice, were reported to be resistant to the direct cytotoxic effect of STZ, but later developed autoimmune diabetes (J. W. Cardinal et al., 2001, Mol.Cell.Biol. 231,5605-5613). We found that Aag(-/-) mice treated with a single high dose of STZ were protected from widespread beta-cell necrosis and diabetes. However, moderate levels of beta-cell apoptosis were observed in the Aag(-/-) STZ-treated mice. While mice became glucose impaired for the duration of study (14 months after STZ injection), overt diabetes did not develop. We conclude that an autoimmune response is not initiated in Aag(-/-) mice in response to beta-cell apoptosis. Furthermore, tumor development is not observed in Aag-/- treated mice, suggesting that N3-methyladenine adducts that accumulate in the genome may not be promutagenic in beta-cells.