Diadenosine tetraphosphate as a signal molecule linked with the functional state of rat liver

Diadenosine 5',5"'-P1,P4-tetraphosphate (Ap4A), which has been suggested to be a signal nucleotide involved in positive growth regulation, was determined in rat liver under various conditions using the luciferin/luciferase system. The Ap4A level was 920 pmol/g of wet liver in normal adult rats, but was high at early stages of growth, the maximum value being 1460 pmol/g in 3-wk-old rats. An increase in Ap4A levels preceded deoxyribonucleic acid synthesis in liver after hepatectomy. Ap4A levels were increased 5.5-fold (5125 pmol/g) 24 h after hepatectomy. The range of such increases was closely correlated with the mass of liver removed. Cholestasis produced by bile duct ligation and intraperitoneal injection of D-galactosamine remarkably lowered the Ap4A level to 20% and 42%, respectively; however, the adenosine triphosphate level was only slightly decreased to 65% and 78%, respectively. Fourteen days after bile duct ligation, Ap4A levels fell to less than 220 pmol/g, and the rats could no longer survive partial hepatectomy. These results suggest that hepatic Ap4A levels correlate positively with regenerative activity.