Clobuzarit: Species differences in the morphological and biochemical response of the liver following chronic administration

Clobuzarit is structurally related to a number of hypolipidemic agents which produce characteristic changes in rodent liver morphology and biochemistry. Liver effects were determined in a number of rodents, the albino rat, C57BL 10J mouse, and Syrian hamster, and in other mammals, the beagle dog and marmoset monkey, following chronic (14-day) oral administration of clobuzarit at two dose levels. Expected (peak) serum levels of clobuzarit were achieved in all species except the marmoset in which levels were approximately half those predicted. Dose-dependent enlargement of rat and mouse liver cells (assessed qualitatively by light microscopy) was observed. This finding was accompanied by proliferation of peroxisomes and smooth endoplasmic reticulum (assessed by electron microscopy and enzymatically). In the rat and mouse, the fatty acid oxidation enzyme systems of peroxisomes and endoplasmic reticulum were markedly induced. The hamster showed no increase in liver cell size but there was a limited proliferation of peroxisomes (indicated by electron microscopy and enzymatically) and an increase in endoplasmic reticulum fatty acid oxidase. No proliferative effects were observed in the liver of the dog or marmoset. Lowering of plasma triglycerides and cholesterol was observed in the rat only. The differences in the morphological and biochemical responses to clobuzarit among the species used in this toxicity testing clearly illustrate the problems of predicting effects in man from animal data.