Evidence that the severity of depletion of inorganic phosphate determines the severity of the disturbance of adenine nucleotide metabolism in the liver and renal cortex of the fructose-loaded rat.
To test the hypothesis that in both the liver and renal cortex of the fructose-loaded rat, severity of depletion of inorganic phosphate (P(i)), and not the magnitude of accumulation of fructose-1-phosphate (F-1-P), determines the severity of the dose-dependent reduction of ATP, we intraperitoneally injected fed rats with fructose, 20 and 40 mumol/g, alone, and at the higher load, in combination with (a) sodium phosphate, 20 mumol/g, administered shortly beforehand or subsequently or, (b) adenosine, 2 mumol/g, administered beforehand. The following observations were made: (a) With fructose loading alone, at the higher load, both P(i) and total adenine nucleotides (TAN) were reduced by one third in the renal cortex and (as previously observed) by two thirds in the liver; and at either load, the reduction of ATP (and TAN) and the accumulation of F-1-P were less severe in the renal cortex than in the liver. (b) Prior phosphate loading largely prevented the reductions of ATP and TAN in the renal cortex and significantly attenuated them in the liver, yet doubled the renal cortical accumulation of F-1-P. (c) Adenosine loading substantially attenuated the reductions of ATP, TAN, and P(i) only in the renal cortex. (d) ATP varied directly with P(i) (P < 0.001, r = 0.98) in the domain of control and reduced values of P(i) taken from both liver and renal cortex. (e) As judged from tissue and plasma concentrations of fructose and glucose, and tissue concentrations of fructose-6-phosphate and glucose-6-phosphate, the rate at which the renal cortex and liver converted fructose to glucose was much lower at the higher fructose load. (f) Prior phosphate loading prevented this decrease in rate in the renal cortex and attenuated it in the liver; adenosine loading attenuated it only in the renal cortex. We conclude that in both the renal cortex of the fructose-loaded rat: (a) Depletion of P(i) is critical to the causation of the reductions in both ATP and TAN and, at the higher fructose load, of a decrease in the rate at which ATP is regenerated. (b) The severity of depletion of P(i) determines the severity of these disturbances. (c) By differentially mitigating the depletion of P(i), prior phosphate loading largely prevents these disturbances in the renal cortex, and attenuates them in the liver; and adenosine loading attenuates them only in the renal cortex. The findings provide some basis for the observation that in patients with hereditary fructose intolerance experimentally exposed to fructose, prior loading with sodium phosphate substantially attenuates the renal but not hepatic dysfunction.