Hydrogen peroxide metabolism during peroxisome proliferation by fenofibrate

Abstract

Fenofibrate, the hypolipidemic drug and peroxisome proliferator, was given to mice (0.23% w/w in the diet) during 1–3 weeks and enzyme activities, H 2O 2 concentration, and H 2O 2 production rate were determined. A maximal increase of 150% in liver/body weight ratio was observed after 3 weeks of treatment. Acyl-CoA oxidase, catalase and uricase activities were increased by 712%, 506% and 41% respectively by treatment with fenofibrate. Se- and non Se-glutathione peroxidase and Mn-superoxide dismutase activities were increased by 331 %, 188% and 130% respectively in the liver of 2 weeks-treated mice. CuZn superoxide dismutase activity was not affected by fenofibrate treatment. H 2O 2 steady-state concentration showed an increase of 89% after 2 weeks of treatment. H 2O 2 production rates, and the steady-state concentrations of the intermediates HO , R and ROO , calculated using experimental data, were higher in the liver of fenofibrate-treated mice than in control animals. According to our findings, the imbalance between H 2O 2 production and its degradation by its metabolizing enzymes during peroxisome proliferation, would result in an increased level of H 2O 2 steady-state concentration, with the resulting oxidative stress which may lead to the generation of oxidative damage and to the induction of liver carcinogenesis.