Concomitant induction of cytosolic but not microsomal epoxide hydrolase with peroxisomal beta-oxidation by various hypolipidemic compounds.
The effects of two cholesterol-lowering (probucol and 1-benzyl-imidazole), three triglyceride- and 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 beta-oxidation and palmitoyl-CoA hydrolase) and two xenobiotic metabolizing enzymes (cytosolic (cEH) and microsomal epoxide hydrolase (mEHb] from the livers of male Fischer F-344 rats were investigated. With the exception of probucol and acetylsalicylic acid, 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 beta-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 beta-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 beta-oxidation and palmitoyl-CoA hydrolase activity, but very dissimilar for mEHb, which upon treatment with any of the triglyceride-lowering compounds was either not or only minimally (less than 1.5-fold) induced. 1-Benzylimidazole possessing exclusively cholesterol-lowering activity increased mEHb much more than either cEH or peroxisomal beta-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.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D002994:Clofibrate / Q000494:pharmacology; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D004851:Epoxide Hydrolases / Q000096:biosynthesis*; D005233:Fatty Alcohols / Q000494:pharmacology; D011345:Fenofibrate / Q000494:pharmacology; D006529:Hepatomegaly / Q000139:chemically induced; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D008099:Liver / Q000201:enzymology / Q000648:ultrastructure; D008297:Male; D008830:Microbodies / Q000187:drug effects / Q000378:metabolism*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D010084:Oxidation-Reduction; D010170:Palmitoyl-CoA Hydrolase / Q000378:metabolism; D011341:Probucol / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344
D005233:Fatty Alcohols; D000960:Hypolipidemic Agents; D007093:Imidazoles; C004568:tiadenol; C017062:1-benzylimidazole; D010170:Palmitoyl-CoA Hydrolase; D004851:Epoxide Hydrolases; D002994:Clofibrate; D011341:Probucol; D001241:Aspirin; D011345:Fenofibrate