Induction of an experimental phenylketonuria-like condition in infant rats during the first 2 weeks after birth

The objective of this study is to induce the primary characteristics of phenylketonuria (PKU) in infant rats during the first 2 wk after birth. The critical biochemical parameter in the development of PKU is the elevation of plasma phenylalanine while tyrosine is maintained at a relatively low level. A PKU-like condition was induced in infant rats during the first 2 wk after birth using a modification of our previously published procedure for the development of a temporary (1 to 3 days) PKU-like condition. Phenylalanine was administered by stomach intubation every 6 h (starting at 6:00 AM) at a dose level of 400 mg/kg body weight (after birth—day 2 through 5) and 500 mg/kg body weight (day 6 through 14). Amethopterin was given at 0.00625 or 0.0125 mg/kg body weight (day 3 through 14) and p-chlorophenylalanine at 50 mg/kg body weight (day 5 through 14) at 9:00 AM and 9:00 PM. At the times measured (6, 10, and 14 days) plasma phenylalanine/tyrosine ratios were elevated from a normal value of one or less to values ranging from 6 to 15. During the 2nd wk after birth a staggering gait, abnormal stance and decreased social behavior were also observed. None of these PKU-like characteristics were apparent in the three control groups receiving 1) no phenylalanine or inhibitors, 2) phenylalanine alone, or 3) inhibitors alone. The establishment of these primary biochemical characteristics of phenylketonuria by stomach intubation of phenylalanine and a combination of low dose levels of enzyme inhibitors to infant rats provides an experimental system which should be valuable for extensive biochemical, histological, and behavioral studies in PKU.