Cox J W, Ulrich R G, Wynalda M A, McKenna R, Larsen E R, Ginsberg L C, Epps D E
Drug Metabolism Research, Upjohn Co., Kalamazoo, MI 49001.
Biochem Pharmacol. 1989 Oct 15;38(20):3535-41. doi: 10.1016/0006-2952(89)90125-1.
Trospectomycin sulfate is an experimental aminocyclitol antibiotic which has been shown previously to induce the formation of cytoplasmic lamellar bodies in rat and dog liver in subchronic experiments. The effect of repeated daily administration of trospectomycin sulfate on hepatic phospholipid levels and activities of marker enzymes for subcellular organelles was examined. Rats were treated for 30 or 90 days with 0, 50, or 250 mg/kg/day of trospectomycin sulfate prior to being killed, and another group was dosed for 90 days and then allowed to recover for 79 days prior to sacrifice. Transmission electron microscopy showed the presence of lamellar bodies in hepatocytes in both 50 and 250 mg/kg groups at 90 days but no other apparent changes in cellular morphology. Total phospholipids were increased significantly (1.6-fold) only at 90 days (P less than 0.01) and only in the 250 mg/kg group. Phosphatidylcholine, phosphatidylinositol, and two acidic lysosomal phospholipids, bis(monoacylglycero)phosphate and acylphosphatidylglycerol, accounted for 42, 35, and 21% of the increase in total phospholipids. Changes in the activities of marker enzymes were generally confined to the 250 mg/kg group at 90 days, with the largest and most significant increases being in the lysosomal enzymes acid phosphatase and hexosaminidase (P less than 0.01). Levels of all phospholipids and marker enzymes, with the exception of succinate dehydrogenase, were not significantly different from controls 79 days after cessation of dosing, and lamellar bodies had disappeared. We conclude that repeated trospectomycin sulfate treatment in rat induces a reversible, dose- and time-dependent lysosomal phospholipidosis in liver which is characterized by an increase in lysosomal enzymes and selected anionic phospholipids.
硫酸大观霉素是一种实验性氨基环醇类抗生素，此前在亚慢性实验中已显示可诱导大鼠和犬肝脏中细胞质板层小体的形成。研究了每日重复给予硫酸大观霉素对肝磷脂水平和亚细胞器标记酶活性的影响。大鼠在处死前分别用0、50或250mg/kg/天的硫酸大观霉素治疗30天或90天，另一组给药90天，然后在处死前恢复79天。透射电子显微镜显示，90天时50mg/kg和250mg/kg组的肝细胞中存在板层小体，但细胞形态无其他明显变化。总磷脂仅在90天时显著增加（1.6倍）（P<0.01），且仅在250mg/kg组中增加。磷脂酰胆碱、磷脂酰肌醇以及两种酸性溶酶体磷脂，双（单酰甘油）磷酸酯和酰基磷脂酰甘油，分别占总磷脂增加量的42%、35%和21%。标记酶活性的变化一般局限于90天时的250mg/kg组，溶酶体酶酸性磷酸酶和己糖胺酶的增加最大且最显著（P<0.01）。除琥珀酸脱氢酶外，所有磷脂和标记酶的水平在停药79天后与对照组无显著差异，且板层小体已消失。我们得出结论，大鼠反复用硫酸大观霉素治疗可诱导肝脏中可逆的、剂量和时间依赖性的溶酶体磷脂沉积症，其特征是溶酶体酶和选定的阴离子磷脂增加。
