Comparison of α-methylphenylalanine and p-chlorophenylalanine as inducers of chronic hyperphenylalaninaemia in developing rats

Abstract

.alpha.-Methylphenylalanine is a very weak competitive inhibitor of rat liver phenylalanine hydroxylase in vitro but a potent suppressor in vivo. The loss of the hepatic activity (the renal one is unaffected) becomes maximal (70-75% decrease; cf. control) 18 h after the administration (per 10 g body wt) of 24 .mu.mol of .alpha.-methylphenylalanine with or without 52 .mu.mol of phenylalanine. Chronic suppression of hepatic phenylalanine hydroxylase was obtained by injections of .alpha.-methylphenylalanine plus phenylalanine to suckling rats, and by their addition to the diet after weaning. A series of comparisons of the effects of this treatment, and one with p-chlorophenylalanine was then carried out. In both cases there was a rise (1.3- to 2-fold) in phenylalanine-pyruvate aminotransferase activity (but no change in 4 other enzyme activities) in the liver; in brain there was a rise in phosphoserine phosphatase activity, but the total activity and subcellular distribution of 9 enzymes revealed no other abnormalities in cerebral development. Striking increases in the concentration of plasma phenylalanine during 26 of the 31 experimental days (with a transient fall at 18-22 days) were maintained by treatment with both analogs plus phenylalanine. p-Chlorophenylalanine-treated animals had a 30-60% mortality rate and 27-52% decrease in body weight. Developing rats treated with .alpha.-methylphenylalanine, showing no growth deficit or signs of toxicity (e.g., cataracts), appear to be a more suitable model for the human disease of phenylketonuria. Their plasma phenylalanine concentrations exhibited at least 20- to 40-fold increases during 50% of each of the 1st 18 days of life, and 30-fold after weaning.