HYDROGEN-PEROXIDE METABOLISM DURING PEROXISOME PROLIFERATION BY FENOFIBRATE

Fenofibrate, the hypolipidemic drug and peroxisome proliferator, was g iven to mice (0.23% w/w in the diet) during 1-3 weeks and enzyme activ ities, H2O2 concentration, and H2O2 production rate were determined. A maximal increase of 150% in liver/body weight ratio was observed afte r 3 weeks of treatment. Acyl-CoA oxidase, catalase and uricase activit ies were increased by 712%, 506% and 41% respectively by treatment wit h fenofibrate. Se- and non Se-glutathione peroxidase and Mn-superoxide dismutase activities were increased by 331%, 188% and 130% respective ly in the liver of 2 weeks-treated mice. Cu-Zn superoxide dismutase ac tivity was not affected by fenofibrate treatment. H2O2 steady-state co ncentration showed an increase of 89% after 2 weeks of treatment. H2O2 production rates, and the steady-state concentrations of the intermed iates HO, R and ROO, calculated using experimental data, were higher i n the liver of fenofibrate-treated mice than in control animals. Accor ding to our findings, the imbalance between H2O2 production and its de gradation by its metabolizing enzymes during peroxisome proliferation, would result in an increased level of H2O2 steady-state concentration , with the resulting oxidative stress which may lead to the generation of oxidative damage and to the induction of liver carcinogenesis.