Phenylalanine Tolerance Tests in Simian Primates

Abstract

The metabolism of amino acids by nonhuman mammalian organisms is of interest in evaluating such organisms for use as animal models of human amino acid metabolic disorders (1). Of particular interest in this regard is phenylketonuria, a genetically-determined deficiency of liver phenylalanine hydroxylase activity that results in impaired metabolism of phenylalanine and has only been discovered in humans. One approach to the production of an animal model for phenylketonuria has been the feeding of large amounts of phenylalanine to rats and monkeys (2, 3). While this reproduces certain biochemical and clinical abnormalities also noted in phenylketonuria, many other characteristics, including the high tyrosine concentrations and the significant phenylalanine hydroxylase activity (3, 4) are distinctly different from human phenylketonuria. Two strains of mice have been reported to have deficient metabolism of phenylalanine (5, 6). However, the “dilute-lethal”strain (so named from its dilute hair color and early death of homozygotes) has recently been shown to metabolize phenylalanine indistinguishably from other mouse genotypes when on a normal diet (7); and in the “wabbler-lethal”strain (with defects in gait and lethality in homozygotes) the plasma phenylalanine concentrations and the plasma phenylalanine: tyrosine ratios are much lower than in human phenylketonuria. In addition the liver phenylalanine hydroxylase activity in this latter strain is much higher in relation to controls than is the case in human phenylketonuria (6). Consequently, there is still a need to develop a genetically-determined animal model for phenylketonuria.

One approach to the production of inherited phenylketonuria in animals is the purposeful mating of known heterozygotes for this disorder. Certain studies in humans have indicated that intravenous phenylalanine tolerance tests are useful in differentiating heterozygotes for phenylketonuria from normal individuals (8-10). For several years, therefore, we have employed intravenous phenylalanine tolerance tests as a technique for identifying primate carriers of the mutant gene for phenylketonuria for the purposes of mating these animals.