Bile acid secretion during rat liver carcinogenesis

Retro-differentiation of liver parenchyma during neoplastic precesses is ch aracterized by the expression of tumor antigens, such as alpha-fetoprotein and the placental isoenzyme of glutathione-S-transferase (GST-P). To invest igate whether this may also affect a typical liver function such as bile ac id secretion was the aim of this work. Rat hepatocarcinogenesis was induced by diethylnitrosamine (i.p., 200 mg/Kg body weight at day 0) and promoted by two-thirds partial hepatectomy (at day 21) plus 2-acetamidofluorene admi nistration (50 mg/Kg body weight, subcutaneously, twice a week from day 14 to day 35). In order to carry out planimetric measurements of neoplastic ti ssue after immunohistochemical staining, a novel monoclonal antibody (MAb 1 4.1.3) against GST-P with no cross-reactivity against the major liver isofo rm of GST (GST-H) was raised. Analysis of total biliary bile acid output us ing the 3 alpha-hydroxysteroid dehydrogenase method indicated that a signif icant reduction (-26%) occurred during the formation of GST-P-positive foci (12 wk). This was restored to normal values during adenoma formation (16-2 0 wk), but decreased again during carcinoma transformation (32 wk). These c hanges were not parallel to that observed in bile now, which was progressiv ely but slightly decreased throughout the whole period under study. HPLC an alysis of bile samples collected for 1 h at different time points during he patocarcinogenesis revealed that in contrast to what happens during cholest atic disease, a continuous and progressive increase in the cholic acid-to-c henodeoxycholic acid ratio (from 4.4+/-0.5 in control animals to 15.1+/-1.9 in rats with hepatocellular carcinoma) occurs. A significant and transient increase at 16 wk (+120%) in the proportion of bile acids amidated with gl ycine as compared to those conjugated with taurine was also observed. These results indicate that the mechanisms accounting for the secretion of major bile acids are modified differently at various steps of rat Liver tumor de velopment.