Abstract
The effects of two cholesterol-lowering (probucol and 1-benzyl-imidazole), three triglycerideand cholesterol-lowering (clofibrate, tiadenol and fenofibrate) and one triglyceride-lowering (acetylsalicylic acid) compounds on the specific activities of two lipid-metabolizing enzymes (cyanide-insensitive peroxisomal β-oxidation and palmitoyl-CoA hydrolase) and two xenobiotic metabolizing enzymes (cytosolic (cEH) and microsomal epoxide hydrolase (mEH b)) from the livers of male Fischer F-344 rats were investigated. With the exception of probucol and acetylsalicylic add, all compounds tested caused a dose-dependent hepatomegaly. Taken on a weight basis fenofibrate was the most effective inducer, causing a 20-fold induction of peroxisomal β-oxidation, a 13-fold induction of cEH activity and a 16-fold induction of palmitoyl-CoA hydrolase activity. The other compounds with triglyceride-lowering activity also induced cEH as well as peroxisomal β-oxidation and palmitoyl-CoA hydrolase activity. The potency of each individual drug was similar for induction of cEH activity as compared with that of peroxisomal β-oxidation and palmitoyl-CoA hydrolase activity, but very dissimilar for mEH b, which upon treatment with any of the triglyceride-lowering compounds was either not or only minimally (<1.5-fold) induced. 1-Benzylimidazole possessing exclusively cholesterol-lowering activity increased mEH b, much more than either cEH or peroxisomal β-oxidation. The absence of an enhancement of cEH activity in in vitro studies confirmed that the increase in enzyme activity by the test compounds is not caused by activation. cEH activity was also induced in the kidney but only about 2-fold by fenofibrate, tiadenol and acetylsalicylic acid. With hypolipidemic drugs varying in their peroxisome-proliferating potency from inactive to very potent, the effects on peroxisomal β-oxidation and cEH were similar in all instances, whilst the effects on mEH b, could be clearly dissociated. Thus, in the rat a concomitant regulation of cEH with peroxisomal β-oxidation and peroxisome proliferation by hypolipidemic drugs becomes apparent.
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