In order to evaluate the validity of using fructose in total parenteral nutrition, the mechanism of the resultant decrease in hepatic ATP content on fructose loading was examined using perfused rat livers. The ATP content of the livers perfused with fructose at a concentration of 2 mM or less, was about 2.8 mumol/g liver. Perfusion with 3 mM and 5 mM fructose decreased the ATP level to 1.65 and 1.50 mumol/g liver, respectively. Transient suppression of respiration occurred after the liver was perfused with fructose at a concentration of 3 mM or more, but not after 2 mM or less. Perfusion of the liver with fructose caused an accumulation of fructose 1-phosphate and a decrease in Pi. At higher concentrations of fructose, the accumulation of fructose 1-phosphate and the depletion of Pi were greater. The Pi depletion, caused by the accumulation of fructose 1-phosphate, suppressed O2 consumption and subsequently decreased the hepatic ATP content. A stoichiometric relationship was found between the total loss of adenine nucleotides in the liver and the amount of purine catabolites in the perfusate. After the administration of fructose at a concentration of 2 mM or less, however, the amount of remaining intracellular Pi was sufficient to maintain respiration and no decrease in the hepatic ATP content was observed.