Reversible, hepatic, lysosomal phospholipidosis in rat induced by subchronic daily administration of trospectomycin sulfate

Abstract

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 < 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 < 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.