FRUCTOSE-1,6-BISPHOSPHATE PROTECTS AGAINST D-GALACTOSAMINE TOXICITY IN ISOLATED RAT HEPATOCYTES

Incubation of hepatocytes with D-galactosamine (GalN) produced a dose- dependent alteration in cell viability and a fall in ATP and fructose 2,6-bisphosphate (Fru-2,6-P-2) levels. The reduction in Fru-2,6-P-2 ca n be explained by changes in the substrates or modulators of 6-phospho fructo-2-kinase/fructose 2,6-bisphosphatase, because neither the adeno sine 3',5'-cyclic monophosphate level nor the activity ratio of the en zyme was modified. Microcalorimetric measurements showed that GalN pro duced an exothermic peak followed by a progressive decrease in heat di ssipation. Simultaneous administration of GalN and fructose 1,6-bispho sphate (Fru-1,6-P-2) significantly increased cell viability, and conce ntrations of ATP and Fru-2,6-P-2 and led to stable heat production. In the presence of Fru-1,6-P-2 alone, hepatocytes kept ATP and Fru-2,6-P -2 levels constant, whereas they increased the oxygen uptake-to-heat o utput ratio. Our results suggest that GalN initiates the hepatotoxic e ffect by means of an energy-dissipating interaction, produced before i ts metabolism and presumably at the membrane level, whereas Fru-1,6-P- 2 protects the cells against this injury in a way that prevents the in itial interaction and increases the metabolic efficiency of the cell.