PEROXISOME-PROLIFERATING EFFECTS OF FENOPROFEN IN MICE

We report on hepatic effects obtained in vivo by treating mice with di fferent doses of fenoprofen, an arylpropionic acid previously shown to inhibit in vitro peroxisomal very long chain fatty acid oxidation. A strong and dose-related induction of peroxisomal palmitoyl-CoA oxidase , and of carnitine acyltransferase and acyl-CoA hydrolase activities w as recorded in liver homogenates of mice fed diets supplemented with d ifferent contents [0.01, 0.05, 0.1, or 1% (w/w)] of fenoprofen for 6 d . Peroxisomal glycolate oxidase and mitochondrial butyryl-CoA, octanoy l-CoA, and palmitoyl-CoA dehydrogenases were unaffected or increased. Hepatic catalase activity was significantly increased in mice fed the diet with 0.05 and 0.1% fenoprofen but, surprisingly, was not stimulat ed in mice fed the 1% fenoprofen-containing diet. A time-related but u nequal induction of acyl-CoA oxidases and catalase was observed with t he 0.1% fenoprofen diet: at 21 d of treatment, the induction of lignoc eroyl-CoA and palmitoyl-CoA oxidase activities were fivefold stronger than that of catalase activity. In mice treated with 1% fenoprofen for up to 6 d, only acyl-CoA oxidase activities were found to be signific antly increased. Morphometric analysis of the liver peroxisomes in mic e treated with 0.1% fenoprofen evidenced an increase in size, volume d ensity, and surface density along with a reduced ratio between perimet er and area of the peroxisomal profiles. No morphological marker for v ery long chain fatty acid deposition could be detected in livers from fenoprofen-treated animals. Our findings clearly demonstrate that feno profen acts as a peroxisome proliferator in the liver of mice and do n ot support the occurrence of in vivo reduction of very long chain fatt y acid oxidation in liver from treated animals.