INHIBITION INSTEAD OF ENHANCEMENT OF LIPID-PEROXIDATION BY PRETREATMENT WITH THE CARCINOGENIC PEROXISOME PROLIFERATOR NAFENOPIN IN RAT-LIVER EXPOSED TO A HIGH SINGLE-DOSE OF CORN-OIL

Oxidative stress is discussed as a possible hepatocarcinogenic mechani sm of peroxisome proliferators (PP) in rodents and is suggested to res ult from the induction of peroxisomal beta-oxidation (PBOX) by PP. The induced PBOX is assumed to produce excessive H2O2 from the degradatio n of fatty acids, ultimately leading to oxidative stress and lipid per oxidation. In the present short term-study, we attempted to stimulate lipid peroxidation in male Wistar rats by (1) inducing PBOX enzymes wi th the peroxisome proliferator nafenopin at 90 mg/kg body weight per d ay in the diet for 10-11 days, and (2) by supplying the induced PBOX w ith an abundant amount of fatty acid as substrate, using a corn oil ga vage at 20 ml/kg body weight. The corn-oil gavage alone, i.e. without preceding nafenopin treatment, enhanced liver triacylglycerol nine-to tenfold and hepatic lipid peroxidation, measured as thiobarbituric aci d reactive substances (TEARS), was increased 50% compared with control s. Both observations were made after 18 h when the peak elevations occ urred. Upon pretreatment with nafenopin, asssociated with a sevenfold induction of PBOX, the corn oil gavage however caused only a threefold maximal increase in hepatic triacylglycerol, also at the 18 h time-po int; TEARS remained almost at control levels, as monitored at seven ti me points over 24-25 h. These results suggest that nafenopin reduces r ather than enhances lipid peroxidation, despite the provision, in a sh ort term study, of high doses of substrate to the induced enzyme syste m that is hypothetically causing oxidative stress in the liver.