Fibrate treatment does not modify the expression of acyl coenzyme A oxidase in human liver

Clin Pharmacol Ther. 2002 Dec;72(6):692-701. doi: 10.1067/mcp.2002.128605.

Abstract

Background and objectives: 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.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyl-CoA Oxidase
  • Apolipoprotein A-I / blood
  • Apolipoprotein A-I / drug effects
  • Apolipoproteins B / blood
  • Apolipoproteins B / drug effects
  • Bezafibrate / pharmacology
  • Carnitine O-Palmitoyltransferase / drug effects
  • Cholecystectomy
  • Cholelithiasis / surgery
  • Cholesterol, HDL / blood
  • Cholesterol, HDL / drug effects
  • Cholesterol, LDL / blood
  • Cholesterol, LDL / drug effects
  • DNA Primers
  • Female
  • Fenofibrate / pharmacology
  • Gemfibrozil / pharmacology
  • Humans
  • Hypolipidemic Agents / pharmacology*
  • Liver / drug effects*
  • Liver / enzymology
  • Male
  • Middle Aged
  • Oxidoreductases / drug effects*
  • Oxidoreductases / genetics
  • Polymerase Chain Reaction
  • RNA, Messenger / drug effects
  • Receptors, Cytoplasmic and Nuclear / drug effects
  • Stearoyl-CoA Desaturase / drug effects
  • Transcription Factors / drug effects
  • Triglycerides / blood

Substances

  • Apolipoprotein A-I
  • Apolipoproteins B
  • Cholesterol, HDL
  • Cholesterol, LDL
  • DNA Primers
  • Hypolipidemic Agents
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
  • Triglycerides
  • Oxidoreductases
  • Stearoyl-CoA Desaturase
  • Acyl-CoA Oxidase
  • Carnitine O-Palmitoyltransferase
  • Gemfibrozil
  • Fenofibrate
  • Bezafibrate