Ray S D, Sorge C L, Raucy J L, Corcoran G B
College of Pharmacy, University of New Mexico, Albuquerque 87131.
Toxicol Appl Pharmacol. 1990 Nov;106(2):346-51. doi: 10.1016/0041-008x(90)90254-r.
Hepatotoxic doses of acetaminophen cause early impairment of Ca2+ homeostasis in the liver. This in vivo study considers the nucleus as a possible site of lethal Ca2+ action by evaluating whether acetaminophen raises Ca2+ in this compartment, whether DNA becomes altered, and whether DNA changes occur early enough during injury to contribute causally to necrosis. Fed Swiss mice were treated with 600 mg/kg acetaminophen ip and livers and blood samples were collected over time. Total nuclear Ca2+ accumulation and fragmentation damage to DNA showed modest parallel increases between 2 and 6 hr, followed by greater than 200% rises at 12 hr mirroring the appearance of frank liver injury (ALT greater than 10,000 U/liter). However, agarose gel electrophoresis revealed extensive loss of large genomic DNA from 2 hr onward, accompanied by the appearance of periodic DNA fragments. Thus, acetaminophen raised nuclear Ca2+ concentrations and promoted DNA fragmentation in vivo. The considerable cleavage of DNA seen at late times probably resulted from cell death, whereas loss of large genomic DNA from 2 hr onward appeared at an early enough point in time to be a contributing factor in acetaminophen-induced liver necrosis.
对乙酰氨基酚的肝毒性剂量会导致肝脏中钙离子稳态的早期受损。这项体内研究通过评估对乙酰氨基酚是否会使细胞核内的钙离子升高、DNA是否发生改变以及在损伤过程中DNA变化是否足够早地发生以因果关系导致坏死，来将细胞核视为钙离子致死作用的一个可能位点。给喂食的瑞士小鼠腹腔注射600 mg/kg对乙酰氨基酚，并随时间收集肝脏和血液样本。细胞核内钙离子的总积累以及DNA的片段化损伤在2至6小时之间呈现适度的平行增加，随后在12小时时增加超过200%，这与明显的肝损伤（谷丙转氨酶大于10,000 U/升）的出现相一致。然而，琼脂糖凝胶电泳显示从2小时起大片段基因组DNA大量丢失，并伴有周期性DNA片段的出现。因此，对乙酰氨基酚在体内升高了细胞核内钙离子浓度并促进了DNA片段化。后期观察到的大量DNA裂解可能是细胞死亡所致，而从2小时起大片段基因组DNA的丢失在时间上出现得足够早，足以成为对乙酰氨基酚诱导肝坏死的一个促成因素。
