Fibrate treatment does not modify the expression of acyl coenzyme A oxidase in human liver.
OBJECTIVE
Fibrates induce hepatic peroxisome proliferation and carcinogenesis in rodents by activating peroxisome proliferator-activated receptor alpha (PPAR(alpha)). There is no conclusive evidence that humans are unresponsive to peroxisome proliferation, and concern exists about the long-term safety of fibrate treatment.


METHODS
In a university hospital setting, 48 patients with uncomplicated gallstones and a serum level of low-density lipoprotein cholesterol greater than 130 mg/dL were randomly assigned to open-label treatment with bezafibrate (400 mg/d), fenofibrate (200 mg/d), gemfibrozil (900 mg/d), or placebo for 8 weeks before elective cholecystectomy. Serum samples for lipid determinations were obtained at baseline and before surgery. A liver specimen was obtained at operation, and the relative levels of messenger ribonucleic acid (mRNA) for the wild and truncated forms of PPAR(alpha), acyl coenzyme A oxidase, liver carnitine palmitoyltransferase I, apolipoprotein A-I, and stearoyl coenzyme A desaturase were determined.


RESULTS
Fenofibrate, bezafibrate, and gemfibrozil reduced plasma low-density lipoprotein cholesterol levels by 22% (P =.009), 14% (P =.042), and 11% (not significant), respectively. Plasma triglyceride levels decreased significantly (24%-36%; P <.05), whereas high-density lipoprotein cholesterol levels rose nonsignificantly after treatment with the 3 fibrates. Except for a 35% increase of apolipoprotein A-I mRNA after fenofibrate administration (P <.05), none of the individual fibrates induced significant changes in the mRNAs tested, although as a group they increased the mRNA for liver carnitine palmitoyltransferase I by 40%(P =.08; marginally significant).


CONCLUSIONS
Fibrate administration to humans at pharmacologic doses able to activate PPAR(alpha) and to induce a hypolipidemic effect does not increase the hepatic expression of acyl coenzyme A oxidase, a well-known marker of peroxisome proliferation in rodents.
Roglans
Núria
N
Pharmacology Unit, Faculty of Pharmacy, University of Barcelona, Surgical Department and Lipid Clinic, Nutrition and Dietetics Service, Hospital Clínic i Provincial, Spain.
Bellido
Antonia
A
Rodríguez
Cristina
C
Cabrero
Agatha
A
Novell
Ferran
F
Ros
Emilio
E
Zambón
Daniel
D
Laguna
Juan C
JC
D042962:Acyl-CoA Oxidase; D016632:Apolipoprotein A-I / Q000097:blood / Q000187:drug effects; D001055:Apolipoproteins B / Q000097:blood / Q000187:drug effects; D001629:Bezafibrate / Q000494:pharmacology; D002334:Carnitine O-Palmitoyltransferase / Q000187:drug effects; D002763:Cholecystectomy; D002769:Cholelithiasis / Q000601:surgery; D008076:Cholesterol, HDL / Q000097:blood / Q000187:drug effects; D008078:Cholesterol, LDL / Q000097:blood / Q000187:drug effects; D017931:DNA Primers; D005260:Female; D011345:Fenofibrate / Q000494:pharmacology; D015248:Gemfibrozil / Q000494:pharmacology; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D010088:Oxidoreductases / Q000187:drug effects* / Q000235:genetics; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects; D013230:Stearoyl-CoA Desaturase / Q000187:drug effects; D014157:Transcription Factors / Q000187:drug effects; D014280:Triglycerides / Q000097:blood
D016632:Apolipoprotein A-I; D001055:Apolipoproteins B; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D017931:DNA Primers; D000960:Hypolipidemic Agents; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014280:Triglycerides; D010088:Oxidoreductases; D013230:Stearoyl-CoA Desaturase; D042962:Acyl-CoA Oxidase; D002334:Carnitine O-Palmitoyltransferase; D015248:Gemfibrozil; D011345:Fenofibrate; D001629:Bezafibrate