EFFECT OF THE PEROXISOME PROLIFERATOR CIPROFIBRATE ON LIPID-PEROXIDATION AND 8-HYDROXYDEOXYGUANOSINE FORMATION IN TRANSGENIC MICE WITH ELEVATED HEPATIC CATALASE ACTIVITY

Peroxisome proliferators are a group of non-genotoxic hepatic carcinog ens which have been proposed to act by increasing oxidative damage in the liver. To test this hypothesis, we have produced a transgenic mous e line that has elevated catalase activity specifically in the liver. In this study, we have examined if catalase overexpression influences the induction of lipid peroxidation or oxidative DNA damage, two mecha nisms which have been hypothesized to be important in the carcinogenes is by peroxisome proliferators. Transgenic mice or non-transgenic litt er mates were fed either 0.01% ciprofibrate or a control diet for 21 d ays. The activities of fatty acyl CoA oxidase and lauric acid hydroxyl ase were not significantly affected by catalase overexpression, althou gh the ratio of fatty acyl CoA oxidase to catalase was significantly d ecreased in transgenic animals. Hepatic lipid peroxidation was estimat ed by quantifying the concentrations of malondialdehyde and conjugated dienes. Ciprofibrate treatment did not affect either endpoint, but ca talase overexpression increased the concentrations of malondialdehyde tin untreated mice only) and conjugated dienes (in both untreated and ciprofibrate-fed mice). Oxidative DNA damage was estimated by quantify ing 8-hydroxydeoxyguanosine (8-OHdG) by high-performance liquid chroma tography/electrochemical detection. Ciprofibrate ate treatment signifi cantly increased hepatic 8-OHdG concentrations, in agreement with seve ral previous studies, but catalase overexpression did not significantl y affect them, although 8-OHdG concentrations were decreased 50% in un treated mice. These results imply that the metabolism of hydrogen pero xide by catalase is not an important factor in the development of hepa tic lipid peroxidation. The decrease in hepatic 8-OHdG in untreated tr ansgenic mice and the increase seen after ciprofibrate administration imply that hydrogen peroxide is important in the formation of 8-OHdG. While the lack of decreased 8-OHdG levels in ciprofibrate-treated tran sgenic mice does not support this conclusion, it is possible that cata lase levels were not sufficiently high to affect this endpoint, Transg enic mice with higher hepatic catalase activities may be required to r esolve this issue. (C) 1998 Elsevier Science Inc.