Effects of the Hepatocarcinogen Nafenopin, a Peroxisome Proliferator, on the Activities of Rat Liver Glutathione-requiring Enzymes and Catatase in Comparison to the Action of Phénobarbital

The biochemical effects in the livers of male rats of prolonged administration of the experimental hepatocarcinogen nafenopin, a hypolipidemic agent and peroxisome proliferator, were com pared to those of another experimental liver carcinogen, phéno barbital, which acts as a neoplasm promoter. Feeding of nafen opin, 0.03 mmol/kg basal diet for up to 24 weeks increased the numbers of hepatic peroxisomes, increased catalase activity, markedly decreased cytosolic glutathione transferase activities toward two substrates, decreased cytosolic glutathione peroxidase activities toward H2O2 and two organic peroxides, and suppressed the age-related increase in 7-glutamyl transpeptidase activity. In contrast the livers of rats fed an equimolar concentration of phénobarbitaldisplayed increases in cytosolic glutathione transferase activities and enhancement of 7-glutamyl transpeptidase activity but no changes in glutathione peroxidase activities. There was also an enhancement of catalase activity without apparent increase in peroxisome number. Enzyme ki netic analyses revealed that the cytosolic glutathione transferase activities toward two halogenonitrobenzene substrates were inhibited in the rats fed nafenopin and displayed elevated Kmand decreased Vmax.Kinetic studies of glutathione transferase activ ities in which nafenopin was mixed with normal rat liver cytosols in the assay system revealed competitive type inhibition toward 1-chloro-2,4-dinitrobenzene and a noncompetitive type of inhibi tion toward 3,4-dichloronitrobenzene. Likewise activities of glu tathione peroxidases toward H202 and eumene hydroperoxide were suppressed by in vitro addition. Thus the effects of nafen opin and phénobarbitalon liver biochemistry were very different. The inhibition of hepatic biotransformation and scavenger sys tems by nafenopin is suggested to be relevant to its hepatocar-