Formation of myeloid bodies in rat liver lysosomes after chloroquine administration

Abstract

When single daily doses (120 mg/kg) of chloroquine sulphate were given to rats, histochemical and ultrastructural investigations demonstrated a sequence of changes in lysosomes of the liver cell. After the first dose, the liver showed an initial loss of particulate β-glucuronidase and acid phosphatase activities (at 1–3 hours) which was most distinct in the periportal area. By 6–24 hours numerous lysosomes with and without recognizable cytoplasmic organelles (autophagic vacuoles and myeloid bodies, were present. After the second and third doses of chloroquine, the lysosomes increased in size and the majority contained myelin figures. Considerable lysosomal enzyme activity was observed in the periphery of the organelle. Further daily doses produced an increasing amount of undegraded sequestrated material and loss of particulate enzyme staining. There was no demonstrable increase in neutral fat, but a progressive increase in what was probably phospholipid was observed, commencing in those areas of the hepatic lobule showing initial loss of lysosomal enzyme activity. The distributional changes of the phospholipid inclusions correspond closely with those seen for the lysosomal hydrolases. In the highest dosage administered, loss of glycogen occurred in the centrilobular cells, which also showed degenerative changes. We postulate that chloroquine initially labilizes the lysosomal membrane, releasing lysosomal enzymes and initiating autophagy thought responsible for sequenstration of cytoplasmic material. Multiple treatment induces stability of lysosomal membranes and probably impedes entry of enzymes into these organelles, resulting in accumulation of undegraded sequestrated material.