Kamendulis L M, Corcoran G B
Toxicology Program, University of New Mexico College of Pharmacy, Albuquerque.
J Pharmacol Exp Ther. 1994 Dec;271(3):1695-8.
Our working hypothesis states that DNA damage is a critical step in toxic cell death. The DNA hypothesis was tested in cultured mouse hepatocytes by examining whether inhibitors of DNA repair would increase dimethylnitrosamine toxicity and DNA damage in parallel. Inhibitors were chosen for selectivity toward DNA polymerase alpha (aphidicolin, myricetin), DNA ligase (ethidium bromide), or multiple repair enzymes (ara-C, doxorubicin). Dimethylnitrosamine caused concentration-dependent DNA damage at 6 hr and cell death at 24 hr (35% ALT release vs. 8.8% in control cultured hepatocytes). Each repair inhibitor increased dimethylnitrosamine-induced DNA damage and toxic cell death in parallel. Doxorubicin maximally elevated DNA fragmentation and toxicity (57% ALT release). Repair inhibitors alone failed to damage DNA or cause cell death in this model system. These data support the hypothesis that DNA damage is an early causal event in toxic cell death caused by alkylating hepatotoxicants.
我们的工作假设表明，DNA损伤是毒性细胞死亡的关键步骤。通过检查DNA修复抑制剂是否会同时增加二甲基亚硝胺毒性和DNA损伤，在培养的小鼠肝细胞中对DNA假设进行了测试。选择对DNA聚合酶α（阿非迪霉素、杨梅素）、DNA连接酶（溴化乙锭）或多种修复酶（阿糖胞苷、阿霉素）具有选择性的抑制剂。二甲基亚硝胺在6小时时引起浓度依赖性DNA损伤，在24小时时导致细胞死亡（35%的谷丙转氨酶释放，而对照培养肝细胞中为8.8%）。每种修复抑制剂均同时增加了二甲基亚硝胺诱导的DNA损伤和毒性细胞死亡。阿霉素最大程度地提高了DNA片段化和毒性（57%的谷丙转氨酶释放）。在该模型系统中，单独使用修复抑制剂未能损伤DNA或导致细胞死亡。这些数据支持了DNA损伤是由烷基化肝毒物引起的毒性细胞死亡中的早期因果事件这一假设。
