A review of drug-induced lysosomal disorders of the liver in man and laboratory animals.

Lysosomotropic agents are selectively taken up into lysosomes following their administration to man and animals [de Duve et al. (1974) Biochem. Pharmacol. 23:2494-2531] The effects of lysosomotropic drugs studied in vivo and in vitro can be used as models of lysosomal storage diseases. These agents include many drugs still used in clinical medicine: aminoglycosides used in antibiotics [Tulkens (1988)]; phenothiazine derivatives; such antiparasitic drugs as chloroquine and suramin; antiinflammatory drugs like gold sodium thiomalate; and cardiotonic drugs like sulmazol [Schneider (1992) Arch. Toxicol. 66:23-33]. Side-effects to these drugs can be caused by their lysosomotropic properties. In addition to drugs, other compounds to which man and animals are exposed (e.g., metals, cytostatics, vitamins, hormones) are also lysosomotropic. Liver cells, especially Kuppfer cells, are known to accumulate lysosomotropic agents. Here we review studies which evaluate lysosomal changes in the liver following administration of lysosomotropic agents to experimental animals, and relate them to toxic side-effects or pharmacological action, as was suggested by de Duve et al. (1974). Common features of lysosomal changes include, the overload of liver lysosomes by non-digestible material; increased size and number of liver lysosomes; inhibition of several lysosomal enzymes; secondary increase in the activity of some lysosomal enzymes; increased autophagy, and fusion disturbances. There was no significant change in endocytosis, except for an increase in the Triton WR 1339 model.