Peroxisome-proliferating effects of fenoprofen in mice.
We report on hepatic effects obtained in vivo by treating mice with different 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 was recorded in liver homogenates of mice fed diets supplemented with different contents [0.01, 0.05, 0.1, or 1% (w/w)] of fenoprofen for 6 d. Peroxisomal glycolate oxidase and mitochondrial butyryl-CoA, octanoyl-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 stimulated in mice fed the 1% fenoprofen-containing diet. A time-related but unequal induction of acyl-CoA oxidases and catalase was observed with the 0.1% fenoprofen diet: at 21 d of treatment, the induction of lignoceroyl-CoA and palmitoyl-CoA oxidase activities were five-fold 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 significantly increased. Morphometric analysis of the liver peroxisomes in mice treated with 0.1% fenoprofen evidenced an increase in size, volume density, and surface density along with a reduced ratio between perimeter and area of the peroxisomal profiles. No morphological marker for very long chain fatty acid deposition could be detected in livers from fenoprofen-treated animals. Our findings clearly demonstrate that fenoprofen acts as a peroxisome proliferator in the liver of mice and do not support the occurrence of in vivo reduction of very long chain fatty acid oxidation in liver from treated animals.
De Craemer
D
D
Menselijke Anatomie & Embryologie, Vrije Universiteit Brussel, Belgium.
Van den Branden
C
C
Pauwels
M
M
Vamecq
J
J
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002333:Carnitine Acyltransferases / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D005279:Fenoprofen / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008830:Microbodies / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D009929:Organ Size / Q000187:drug effects; D010088:Oxidoreductases / Q000378:metabolism; D010170:Palmitoyl-CoA Hydrolase / Q000378:metabolism; D013997:Time Factors
D016861:Cyclooxygenase Inhibitors; D010088:Oxidoreductases; C028427:palmitoyl CoA oxidase; D002333:Carnitine Acyltransferases; D010170:Palmitoyl-CoA Hydrolase; D005279:Fenoprofen