Comparative ultrastructural study of rat hepatocytes after treatment with the hypolipidemic agents probucol, clofibrate, and fenofibrate

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Abstract
Experimental findings are reported for 2 similarly conducted studies. One was designed to compare rat liver cell ultrastructure during and after 91 days of dosing with probucol, a hypocholesterolemic agent, and clofibrate, a hypolipidemic drug known to elicit marked alteration of rat hepatocellular morphology. The 2nd was designed to similarly assess male rats after 28 days of treatment with the hypolipidemic agent fenofibrate. Diet mixes for these studies were prepared to attain dosage levels of approximately 500 mg/kg per day for probucol, 250 mg/kg per day for clofibrate and 100 mg/kg per day for fenofibrate. Control rats were given untreated basal ration. Weekly adjustments in dietary concentrations were made in accordance with group mean food consumption and body weight-changes. Probucol and clofibrate treatments produced statistically significant reductions in mean serum cholesterol levels of both sexes after 28 and 91 days of dosing. Only male rats were given fenofibrate, and they exhibited statistically significant cholesterol reductions after 28 days. Clofibrate and fenofibrate administration resulted in marked increases in liver weight/body weight ratios. Probucol had no statistically significant effects on liver weight/body weight ratios after 28 and 91 consecutive days of treatment. Light microscopy of liver sections stained with hematoxylin and eosin revealed an abnormal amount of cytoplasmic granularity within hepatocytes from rats given clofibrate and fenofibrate. The granules were identified by EM and cytochemistry as enlarged, proliferated peroxisomes, a known rat hepatocellular response to treatment with many hypolipidemic drugs. Ultrastructural cytochemistry suggested reduced amounts of catalase in individual peroxisomes after clofibrate and fenofibrate dosing. Liver tissue from rats given probucol showed no abnormal cytoplasmic granularity and, ultrastructurally, no peroxisomal changes. Liver tissues from probucol-treated rats revealed features similar to those encountered in tissues from untreated control animals. Hypocholesterolemic response elicited by probucol treatment does not involve significant changes in rat liver cell morphology.

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