MODIFICATIONS OF LIVER BILE-ACIDS POOL DURING MODULATION OF RAT HEPATOCARCINOGENESIS BY PHENOBARBITAL AND NAFENOPIN

As previously demonstrated, chronic administration of phenobarbital (0 .05% in the drinking water) and of nafenopin (0.1% in the diet) increa ses the incidence and the kinetics of appearance of liver cancers. If bile acids play a key role in liver carcinogenesis, it might thus be e xpected that treatments like phenobarbital or nafenopin, which positiv ely modulate that process, also modify their hepatic pool. The aim of the present study was to analyze the modifications of the liver bile a cid pool during the modulation of liver carcinogenesis by phenobarbita l and nafenopin. The animals were submitted to the hepatocarcinogenic initiation-selection (IS) procedure adapted from Solt and Farber. As c ompared to basal diet, the chronic feeding of phenobarbital significan tly increased the total concentrations of liver bile acids both at wee ks 9 and 17. That increase was mainly due to a change in the concentra tion of beta-muricholic acid and hyodeoxycholic acid and, to a lesser extent, of chenodeoxycholic acid and alpha-muricholic acid. In contras t, feeding a diet containing nafenopin led to a significant decrease i n the concentration of liver bile acids, due to a complete disappearan ce of chenodeoxycholic acid and muricholic acid, and a decrease in the concentration of hyodeoxycholic acid. Carcinomas appearing in IS phen obarbital-treated rats contain fewer bile acids than the surrounding p arenchyma (because of the decrease in deoxycholic acid and ursodeoxych olic acid) whereas the malignant tumors appearing in IS nafenopin-trea ted rats have essentially the same pattern of bile acids as the surrou nding parenchyma. During modulation of liver carcinogenesis by phenoba rbital and nafenopin, changes in bile acid metabolism definitively tak e place but they are both quantitatively and qualitatively different. Therefore, the perturbations of liver bile acid homeostasis occurring in such a carcinogenic protocol do not seem to be implicated in the po sitive modulation induced by phenobarbital or nafenopin treatment.