Evidence for dual effect of bile acids on thymidine anabolism and catabolism by the regenerating rat liver

Abstract

Bile acids have been reported to modify DNA synthesis by rodent livers in regeneration, which may be due in part to their ability to interact with the machinery responsible for deoxyribonucleotide synthesis. The aim of this work was to gain information on the effect of taurocholate (TC) on both anabolic and catabolic pathways accounting for the fate of [methyl-14C]thymidine in the liver of two-third hepatectomized rats. Using high-pressure liquid chromatography, the soluble fraction of liver homogenate was used to measure the ability of TC to modify both the rate of thymidine monophosphate formation from thymidine — i.e., thymidine kinase (TK) activity — and the rate of thymidine release from thymidine, which is the result of at least three different reactions catalyzed by thymidine phosphorylase, nucleosidase and nucleoside deoxyribosyl transferase. TC was found to induce a dose-dependent inhibition of both processes. The nature of this inhibition seems to be in part competitive. Apparent Ki value were 1.5 mM for TK and 4 mM for thymidine release. These inhibitory effects were mimicked by glycocholate but not by taurine. To investigate the relevance of the TC-induced modification of anabolism and catabolism in the whole organ, experiments on regenerating perfused rat livers were carried out. The donors underwent two-third hepatectomy 24 h before liver isolation. They were either fasted during this period (F) or allowed free access to food (NF). DNA synthesis, as measured by [methyl-14C]thymidine incorporation into DNA, was significantly increased in both groups, as compared with control non-hepatectomized animals. However, enhancement in DNA synthesis in group F was only 50% of the value found in the NF group. Intravenous 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 radiolabelled metabolites contained in the non-DNA fraction of liver homogenate, consistent with a marked inhibition of thymidine catabolism. These results 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 thymidine 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 contrast, under depressed DNA synthesis due to fasting, the overall effect of TC is a partial recovery of this process.