Tilorone-induced lysosomal storage mimicking the features of mucopolysaccharidosis and of lipidosis in rat liver.
This ultrastructural and histochemical study deals with the lysosomal storage phenomena occurring in the rat liver after repeated oral administration of tilorone, an agent with anti-tumor and anti-viral activities. In the sinusoidal endothelium and in Kupffer cells, the lysosomes were changed into large vacuoles which contained material with the histochemical characteristics of acid glycosaminoglycans. The alterations closely resembled those previously observed in the splenic red pulp of tilorone-treated rats. In hepatocytes, the lysosomes were converted into large multilamellated inclusions indicating storage of polar lipids. The results show that, in the rat liver, tilorone induces cellular alterations mimicking those of inherited mucopolysaccharidoses and lipidoses. After discontinuing drug treatment the two storage phenomena gradually faded at different rates: The lipidosis disappeared within 2 to 4 weeks, whilst mucopolysaccharidosis-like changes were still found 15 weeks after drug withdrawal. The occurrence of lipidosis is not surprising, since by its molecular structure tilorone can be regarded as belonging to the group of amphiphilic cationic drugs which often have this side effect. Much more surprising is the occurrence of mucopolysaccharidosis-like alterations. The exact biochemical identification of the polyanionic storage material and the molecular mechanisms responsible for this drug side effect remain to be established.
D000818:Animals; D004727:Endothelium / Q000648:ultrastructure; D005260:Female; D005449:Fluorenes / Q000633:toxicity*; D007728:Kupffer Cells / Q000648:ultrastructure; D008064:Lipidoses / Q000139:chemically induced*; D008099:Liver / Q000187:drug effects / Q000648:ultrastructure; D008854:Microscopy, Electron; D009083:Mucopolysaccharidoses / Q000139:chemically induced*; D051381:Rats; D011919:Rats, Inbred Strains; D013194:Staining and Labeling; D013994:Tilorone / Q000633:toxicity*
D005449:Fluorenes; D013994:Tilorone