EVIDENCE FOR DUAL EFFECT OF BILE-ACIDS ON THYMIDINE ANABOLISM AND CATABOLISM BY THE REGENERATING RAT-LIVER

Bile acids have been reported to modify DNA synthesis by rodent livers in regeneration, which may be due in part to their ability to interac t with the machinery responsible for deoxyribonucleotide synthesis. Th e aim of this work was to gain information on the effect of taurochola te (TC) on both anabolic and catabolic pathways accounting for the fat e of [methyl-C-14]thymidine in the liver of two-third hepatectomized r ats. Using high-pressure liquid chromatography, the soluble fraction o f liver homogenate was used to measure the ability of TC to modify bot h the rate of thymidine monophosphate formation from thymidine - i.e., thymidine kinase (TK) activity - and the rate of thymidine release fr om thymidine, which is the result of at least three different reaction s catalyzed by thymidine phosphorylase, nucleosidase and nucleoside de oxyribosyl transferase. TC was found to induce a dose-dependent inhibi tion of both processes. The nature of this inhibition seems to be in p art competitive. Apparent Ki value were 1.5 mM for TK and 4 mM for thy midine release. These inhibitory effects were mimicked by glycocholate but not by taurine. To investigate the relevance of the TC-induced mo dification of anabolism and catabolism in the whole organ, experiments on regenerating perfused rat livers were carried out. The donors unde rwent two-third hepatectomy 24 h before liver isolation. They were eit her fasted during this period (F) or allowed free access to food (NF). DNA synthesis, as measured by [methyl-C-14]thymidine incorporation in to DNA, was significantly increased in both groups, as compared with c ontrol non-hepatectomized animals. However, enhancement in DNA synthes is in group F was only 50% of the value found in the NF group. Intrave nous TC administration before and/or during liver perfusions induced a dose-dependent recovery of DNA synthesis in the F group. This effect was accompanied by opposed modifications in the amount of radiolabelle d metabolites contained in the non-DNA fraction of liver homogenate, c onsistent with a marked inhibition of thymidine catabolism. These resu lts suggest that, in addition to the previously reported effects of TC on thymidine anabolism, bile acids are also able to affect thymidine catabolism. The overall results of this dual effect on the fate of thy midine in the regenerating rat liver depend on the metabolic situation . Under circumstances of no nutrient restriction, the effect of TC is characterized by inhibition of thymidine incorporation into DNA. By co ntrast, under depressed DNA synthesis due to fasting, the overall effe ct of TC is a partial recovery of this process.