Polyamine Metabolism and DNA Synthesis in Regenerating Rat Liver12

Abstract

The induction of hepatic ornithine decarboxylase [EC 4.1.1.17] is one of the earliest detectable events in liver regeneration. Administration of DL-α-hydrazino-δ-aminovaleric acid (DL-HAVA), a competitive inhibitor of ornithine decarboxylase, markedly inhibited the rise in the putrescine level and increase in DNA synthesis in rat liver after partial hepatectomy. DL-HAVA also depressed the rises in the activities of thymidinc kinase [EC 2.7.1.21] and thymidylate synthetase [EC 2.1.1.45] in regenerating rat liver, resulting in a large decrease in the hepatic deoxythymidine triphosphate (dTTP) pool that normally expands in response to the operation, though the induction of DNA polymerase [EC 2.7.7.7] was little affected by the inhibitor. These inhibitions by DL-HAVA were effectively reversed by the administration of putrescine, but not 1,3-diaminopropane or cadaverine. Administration of 1,3-diaminopropane, which inhibits the induction of ornithine decarboxylase, caused metabolic alterations in regenerating rat liver similar to those produced by DL-HAVA. Injection of aminoguanidine, a potent inhibitor of diamine oxidase [EC 1.4.3.6], resulted in increased putrescine accumulation and then increased DNA synthesis in the regenerating liver. These results strongly suggest that putrescine synthesis is a prerequisite for liver regeneration and that polyamine(s) is involved in the synthesis of dTTP (and consequently DNA synthesis) in the liver after partial hepatectomy.