Cox J W, Ulrich R G, Larson P G, Cramer C T
Pharmaceutical Research and Development Division, Upjohn Company, Kalamazoo, MI 49001.
Pharmacol Toxicol. 1988 May;62(5):337-43. doi: 10.1111/j.1600-0773.1988.tb01900.x.
The formation of multilamellar inclusion bodies in cytoplasm is a generalized cellular response to treatment with a variety of chemical agents. The present study was conducted to determine if a correlation exists between acute lamellar body induction potency and cytotoxicity in the perfused rat liver. Livers were perfused for 3 hrs with various concentrations of erythromycin, gentamicin, sulfate, or trospectomycin sulfate, all of which are known to produce lamellar bodies in the rat in vivo. At the end of the experiments, the livers were perfusion fixed for transmission electron microscopy. Based on the bile flow rate, perfusion rate at constant pressure, and cytoplasmic enzyme release, neither gentamicin nor trospectomycin was hepatotoxic at concentrations up to 1.8 mM, whereas erythromycin was toxic at 0.1 mM. Gentamicin caused no ultrastructural changes compared to controls, but trospectomycin caused the dose-dependent formation of lamellar bodies in hepatocytes without other cytoplasmic alterations. Erythromycin caused cellular degeneration accompanied by an increase in the number of secondary lysosomes, but these lacked lamellated inclusions. It is concluded that hepatic lamellar bodies can be induced in acute ex vivo experiments, but that their formation does not appear to be linked with acute cytotoxicity.
细胞质中多板层包涵体的形成是细胞对多种化学试剂处理的一种普遍反应。本研究旨在确定在灌注大鼠肝脏中，急性板层体诱导能力与细胞毒性之间是否存在相关性。用不同浓度的红霉素、庆大霉素、硫酸盐或硫酸曲古霉素灌注肝脏3小时，所有这些药物在大鼠体内均已知会产生板层体。实验结束时，对肝脏进行灌注固定以用于透射电子显微镜检查。根据胆汁流速、恒压灌注速率和细胞质酶释放情况，在浓度高达1.8 mM时，庆大霉素和硫酸曲古霉素均无肝毒性，而红霉素在0.1 mM时具有毒性。与对照组相比，庆大霉素未引起超微结构变化，但硫酸曲古霉素导致肝细胞中板层体呈剂量依赖性形成，而无其他细胞质改变。红霉素引起细胞变性，伴有次级溶酶体数量增加，但这些溶酶体缺乏层状包涵体。结论是，在急性离体实验中可诱导肝板层体形成，但其形成似乎与急性细胞毒性无关。
