Male Swiss-Webster mice were fed diets containing four
hypolipidemic agents which are known to induce proliferation of hepatic peroxisomes. Treatment with all four drugs (
clofibrate; its structural analogue,
nafenopin; and two drugs structurally unrelated to
clofibrate,
tibric acid and
Wy-14,643) 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 (twofold to threefold),
alpha-glycerophosphate dehydrogenase (twofold to threefold) and the long-chain
carnitine acyltransferase (twofold to fourfold). Activity of the latter
enzyme, however, is 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.