Inhibition of 3'-methyl-4-dimethylaminoazobenezene-induced hepatocarcinogenesis by portacaval shunt

Abstract

Adult male Sprague Dalwey rats on which end-to-side portacaval shunt (PCS) operation was performed did not hyperplastic nodules and hepatoms when they were fed 3'-methyl-4-dimethylaminoazobenzene in semisynthetic basal diet for periods of up to 169 days. In contrast, all the intact rats fed the same diet for only 75 days, developed hyperplastic nodules in the liver. Transferred to normal pellet for another 25 days, hepatomas developed in 100% of these animals. The amount of protein-bond 3'-Me-DAB was found to be much smaller in operated rats than in intact animals. The glutathione (GSH) level in PCS-operated rats was lower than in intact controsl. A single large dose of 3'-Me-DAB led to the increase of only about 30% in the concentration of GSH during the period of 24-48 h, compared to the increase of 50-100% in non-operated rats. No clear tendency to a gradual increase in the activity of gamma-glutamyl transpeptidase was noted in PCS-operated rats during the period of 5 1/2 months of 3'-Me-DAB feeding. The increase in GT-ase activity never exceeded 30% above the level of GT-ase in the livers of PCS-operated rats fed basal diet without the carcinogen. This striking inhibibiton of GT-ase increase induced by 3'Me-DAB in PCS-operated rats contrasted with an increase of GI-ase activity by 5,000% found in livers of non-operated rats with hyperplastic nodules after 75 days of 3'-Me-DAB feeding and the increase by up to 10,000% in developed hepatomas. These effects and the inhibition of 3'Me-DAB-induced hepatocarcinogenesis, manifested by lack preneoplastic morphologic changes and the absecnce of hepatomas in rats after PCS, can best be explained by functional deficiency of the liver to metabolize the procarcinogen 3'-Me-DAB into an activated carcinogen.