Phenylketonuria in the rat associated with decreased temporal discrimination learning.

Abstract

IN the course of other investigations1 in which tyrosine was injected intraperitoneally it was noted that the level of phenylalanine hydroxylase in the liver of rats was diminished to about one-third the normal value. Since tyrosine added in vitro does not inhibit this enzyme activity2, the results were taken as evidence of product inhibition of enzyme synthesis. It was reasoned that added dietary tyrosine would decrease the enzyme formation and therefore lower the amount of phenylalanine being oxidized to tyrosine; the excess phenylalanine would then be transaminated to phenylpyruvate. Other workers3 had already shown that phenylalanine added to liver slices would also inhibit the oxidation of tyrosine to acetoacetate and fumarate. It seemed worth while therefore to feed various combinations of tyrosine and phenylalanine in order to evaluate metabolic alterations in the rat. Initial experiments with Commercial rat food plus 5 per cent L-tyrosine and 5 per cent DL-phenylalanine resulted in the death of newborn or suckling animals when this diet was fed to the pre-parturient and lactating mothers. The same diet caused death when fed to 21-day-old animals, although animals of the same age grew normally when fed 5 per cent of either amino-acid alone. Reduction of the levels to 2.5 per cent of each amino-acid (and in a later experiment to 3.75 per cent each) caused no difficulty since animals fed this diet gained weight at a rate comparable to that of rats on the commercial diet alone. The methods used for the amino-acid analyses and for enzyme assays have been previously listed1. The urinary and blood data are given in Table 1, and the enzymatic data concerned with phenylalanine and tyrosine metabolism are given in Table 2.