Drug-induced lysosomal disorders in laboratory animals: new substances acting on lysosomes

Several substances with lysosomotropic activity were investigated in toxicological studies. AR-L 115 BS (sulmazol, a cardiotonic agent) was tested on beagle dogs; HX-CH 44 BS (a beta-blocker) and SX-AB 1316 SE (an antithrombotic agent) were tested on rats, and AF-CX 1325 XX (an antiepileptic agent) was tested on both rats and beagle dogs. All organ systems were examined morphologically by light and/or electron microscopy. When an increase in the number of lysosomes occurred this was confirmed by the pigment scheme according to Krutsay (1971) as well as by the detection of acid phosphatase and compared with earlier histochemical results. At higher dosages, all substances caused very marked proliferation of lysosomes in the liver and/or kidneys. HX-CH 44 BS also caused such proliferation in striated muscles and in the lungs. A brown discolouration of the kidneys was found with sulmazol and AF-CX 1325 XX. This finding corresponded to the microscopically detectable occurrence of numerous lipofuscin granules. The reticulum cells in the lymph nodes of dogs were also affected by AF-CX 1325 XX. It is concluded that the proliferation of lysosomes in various organs after administration of the above-mentioned substances is due to an excess of substance. The increased substance in the body is then stored in the lysosomes. With HX-CH 44 BS, lysosomal autodigestion of mitochondria in the skeletal musculature and in the alveolar macrophages of the lungs was found. The selective lysosomal incorporation of mitochondria has not been described up to now and in our opinion, this constitutes a special feature. The results otherwise largely correspond to those already described in the literature. Systemic phospholipidosis such as occurs with some other substances was not detectable. The incorporation of the substance causes several types of lysosomal inclusion. Uptake of the substance in lysosomes either leads to overt autodigestion of organelles such as mitochondria (HX-CH 44 BS) or peroxisomes or to residual lysosomes of dense structure which histochemically resemble lipofuscin. SX-AB 1316 SE serves as an example of a substance which is stored directly by lysosomes in crystalline form. Above all, in the liver the substance is taken up not only by the sinusoidal stellate cells but also by hepatocytes.