A Defect in the Metabolism of Tyrosine and Phenylalanine in Premature Infants. I. Identification and Assay of Intermediary Products 12

Abstract

In the course of studies of the urinary excretion of creatinine by premature infants, a number of the infants fed cow's milk were found to excrete a substance which gave the Waffe reaction but which was not creatinine. The interfering chromogen was differentiated from creatinine by its solubility in ether, its lack of adsorption by Lloyd's reagent and its partial destruction by heat (1000 C.) in acid solution. It also gave a yellow color with dinitrobenzoic acid in alkaline solution instead of the purple-rose color given by creatinine (1). Acetone and acetoacetic acid were not present in the urines. This chance discovery initiated the present studies.The fact that the chromogen appeared only in the urine of infants receiving cow's milk diets relatively high in protein (5 grams or more per kgm.) suggested that it might be an intermediary product of protein metabolism. Qualitative and quantitative (2) tests of chromogenic urines revealed usual amounts of amino acids. Qualitative tests for tryptophane and the indole ring were negative. The Millon test for the hydroxyphenyl group was strongly positive, indicating that the intermediary products in the urine were probably derived from the metabolism of tyrosine and possibly of phenylalanine, an hypothesis which was substantiated by feeding observations with pure amino acids. The absence of darkening of the urine during aeration excluded the presence of significant amounts of homogentisic acid (alkaptonuria).Isolation and identification of intermediary metabolites

A Defect in the Metabolism of Tyrosine and Phenylalanine in Premature Infants. Ii. Spontaneous Occurrence and Eradication by Vitamin C 12

“…in the final specimens (J. S.). The excretion of keto acids for individual infants comprised from 15 to 34 per cent of the total hydroxyphenyl compounds, the remaining 66 to 85 per cent being almost entirely p-hydroxyphenyllactic acid (1).…”

“…Since the ingestion of single doses of phenylalanine and tyrosine always increased the excretion of hydroxyphenyl compounds in premature infants on vitamin C-free diets of cow's milk (1), the effect of these amino acids was determined in 2 of the full term infants previously studied (Table II) under similar dietary conditions.…”

“…A detailed description of the method for collecting urine separately from feces in premature infants was given in previous papers (5). Urine was collected quantitatively from all of the infants throughout observations and analyzed at the end of each 24-hour period for the normal urinary constituents listed in the preceding paper (1), for total hydroxyphenyl compounds (tyrosine, p-hydroxyphenyllactic and p-hydroxyphenylpyruvic acids, expressed as tyrosine) (6,7), and for the keto acid alone (p-hydroxyphenylpyruvic acid) (7) by the methods there outlined. The difference between the total tyrosine equivalent and the keto acid afforded a quantitative estimate of p-hydroxyphenyllactic acid (1).…”

Certain Aspects of Tyrosine Metabolism in the Young. I. The Development of the Tyrosine Oxidizing System in Human Liver 1

“…Clinically, it was shown (8,9) that premature infants maintained on a diet high in protein without added ascorbic acid excreted p-hydroxyphenylpyruvic acid in their urine. Similarly, p-hydroxyphenylpyruvic acid was excreted in the urine of scorbutic adults (10,11).…”

Metabolic Studies of Transient Tyrosinemia in Premature Infants

“…Previous studies (1, 15,16,[18][19][20] indicated that it is samples from 16 premature or small for gestational age transient, aggravated by high protein (or high ~h e n~l a l a n i n e neonates, receiving treatment in the Stanford University and tyrosine) intake, and that it is prevented by reducing Hospital Nursery. Criteria for entrance t o the study included: protein intake or increasing vitamin C in the diet.…”