Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139, Dortmund, Germany.
Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, 83523, Egypt.
Arch Toxicol. 2024 May;98(5):1533-1542. doi: 10.1007/s00204-024-03705-6. Epub 2024 Mar 11.
Acetaminophen (APAP) is known to cause a breach of the blood-bile barrier in mice that, via a mechanism called futile bile acid (BA) cycling, increases BA concentrations in hepatocytes above cytotoxic thresholds. Here, we compared this mechanism in mice and rats, because both species differ massively in their susceptibility to APAP and compared the results to available human data. Dose and time-dependent APAP experiments were performed in male C57BL6/N mice and Wistar rats. The time course of BA concentrations in liver tissue and in blood was analyzed by MALDI-MSI and LC-MS/MS. APAP and its derivatives were measured in the blood by LC-MS. APAP-induced liver damage was analyzed by histopathology, immunohistochemistry, and by clinical chemistry. In mice, a transient increase of BA in blood and in peri-central hepatocytes preceded hepatocyte death. The BA increase coincided with oxidative stress in liver tissue and a compromised morphology of bile canaliculi and immunohistochemically visualized tight junction proteins. Rats showed a reduced metabolic activation of APAP compared to mice. However, even at very high doses that caused cell death of hepatocytes, no increase of BA concentrations was observed neither in liver tissue nor in the blood. Correspondingly, no oxidative stress was detectable, and the morphology of bile canaliculi and tight junction proteins remained unaltered. In conclusion, different mechanisms cause cell death in rats and mice, whereby oxidative stress and a breach of the blood-bile barrier are seen only in mice. Since transient cholestasis also occurs in human patients with APAP overdose, mice are a clinically relevant species to study APAP hepatotoxicity but not rats.
对乙酰氨基酚（APAP）已知可导致小鼠血-胆屏障破裂，通过一种称为无效胆汁酸（BA）循环的机制，使肝细胞内 BA 浓度升高到细胞毒性阈值以上。在这里，我们比较了这种机制在小鼠和大鼠中的作用，因为这两种物种对 APAP 的敏感性有很大的差异，并将结果与现有的人类数据进行了比较。在雄性 C57BL6/N 小鼠和 Wistar 大鼠中进行了剂量和时间依赖性 APAP 实验。通过 MALDI-MSI 和 LC-MS/MS 分析肝组织和血液中 BA 浓度的时间过程。通过 LC-MS 测量血液中的 APAP 和其衍生物。通过组织病理学、免疫组织化学和临床化学分析 APAP 诱导的肝损伤。在小鼠中，BA 在血液和中央周肝细胞中的短暂增加先于肝细胞死亡。BA 的增加与肝组织中的氧化应激以及胆小管的形态受损和免疫组织化学可视化的紧密连接蛋白相一致。与小鼠相比，大鼠对 APAP 的代谢激活减少。然而，即使在导致肝细胞死亡的非常高剂量下，也没有观察到 BA 浓度在肝组织或血液中增加。相应地，没有检测到氧化应激，胆小管和紧密连接蛋白的形态也没有改变。总之，不同的机制导致大鼠和小鼠的细胞死亡，其中氧化应激和血-胆屏障的破裂仅在小鼠中可见。由于在 APAP 过量的人类患者中也会发生短暂的胆汁淤积，因此小鼠是研究 APAP 肝毒性的临床相关物种，但不是大鼠。
