HEPATIC EFFECTS OF HYPOLIPIDEMIC DRUGS (CLOFIBRATE, NAFENOPIN, TIBRIC ACID, AND WY-14,643) ON HEPATIC PEROXISOMES AND PEROXISOME-ASSOCIATED ENZYMES

Abstract

Male Swiss-Webster mice were fed diets containing 4 hypolipidemic agents which are known to induce proliferation of hepatic peroxisomes. Treatment with all 4 drugs (clofibrate; its structural analogue, nafenopin; and 2 drugs structurally unrelated to clofibrate, tibric acid and Wy-14,643 [4-chloro-6-(2,3-xylidino-2-pyrimidinylthio)acetic acid]) produced a marked hepatomegaly in the mice. The extent of the increase in liver weight correlated well with the increases in total hepatic DNA and in the collective volume of hepatocyte peroxisomes. Treatment with these drugs also produced similar increases in the activities of peroxisome-associated enzymes. The most dramatic increases were noted in the activities of the short-chain (8- to 26-fold) and medium-chain (4- to 11-fold) carnitine acyltransferase. Significant increases were also noted in the activities of catalase (2-fold to 3-fold), .alpha.-glycerophosphate dehydrogenase (2-fold to 3-fold) and the long-chain carnitine acyltransferase (2-fold to 4-fold). Activity of the latter enzyme was not known to be associated with peroxisome fractions. Concomitant administration of actinomycin D or cycloheximide with a single oral dose of clofibrate diminished the increases in liver weight and carnitine acyltransferase which occurred with clofibrate treatment alone. The finding that the major increase in activity of peroxisome enzymes occurred in those associated with metabolism of acyl CoA groups supports the hypothesis that the hypolipidemic action of the drugs and the proliferation of hepatic peroxisomes are related functions.