Effects of phenylalanine loading on protein synthesis in the fetal heart and brain of rat: an experimental approach to maternal phenylketonuria

Abstract

Pregnant rats were loaded with L-phenylalanine, and the distributions of [14C]leucine and [14C]urea into fetal plasma and tissues were examined. Uptake of [14C]leucine into the supernatant and protein fractions of fetal plasma and tissues was low in the rats loaded with phenylalanine. In contrast, [14C]urea was distributed identically in both groups, indicating that maternal hyperphenylalaninemia did not affect blood flow across the placenta. Administration of phenylalanine and p-chlorophenylalanine produced amino acid imbalance in fetal tissues. Along with these changes, polysomes of the affected fetal heart and brain disaggregated without changes in the ribonuclease activity. These results indicate that high phenylalanine levels in maternal plasma disturb the active transport of amino acids across the placenta, causing an amino acid imbalance and disaggregation of polysomes in fetal heart and brain. These changes may contribute to the congenital heart disease and mental retardation of maternal phenylketonuria.

Significant phenylalanine hydroxylation in vivo in patients with classical phenylketonuria.

“…This decrease presumably reflects the expected decrease in protein turnover in PKU which would be likely to result from lower protein intakes (31) and/or increased phenylalanine concentration (32).…”

Protein Metabolism in Phenylketonuria and Lesch-Nyhan Syndrome

“…More recently, this mechanism has also been suggested to account for congenital defects such as low birth wt and heart malformations in the offspring of PKU mothers (2). The decrease in protein synthesis is presumed to result from the well-documented reduction in blood and brain of concentrations of amino acids other than phenylalanine in PKU (38, 39).…”

“…Free amino acid concentrations have a regulatory role in protein synthesis, with decreased concentrations resulting in decreased polysomal aggregation (8). Inhibition of polysomal aggregation and decreased incorporation of labeled leucine into a wide range of tissues in the animal model of PKU have supported the proposal that decreased protein synthesis is the cause of congenital abnormalities in the offspring of mothers with PKU (2,3,9). Imbalances of a number of amino acids other than phenylalanine are present in peripheral tissues as well as brain in both mother and fetus in the animal PKU model (2), suggesting that disturbances in protein metabolism induced by high phenylalanine concentrations would be likely to be manifest throughout the body.…”

“…2 sis in animal models of PKU (1)(2)(3)(4), which has led to wide acceptance of an etiology involving impaired protein synthesis. Such a mechanism has been used in particular to explain the tissue damage that occurs in maternal PKU.…”

“…These abnormalities appear related to the control of blood phenylalanine levels throughout pregnancy, but especially at conception (5). Animal models of maternal PKU have shown that maternal hyperphenylalaninemia suppresses active transport of amino acids, especially branched-chain amino acids and methionine, across the placenta (2), resulting in amino acid imbalances in fetal plasma and tissues (2,7). Free amino acid concentrations have a regulatory role in protein synthesis, with decreased concentrations resulting in decreased polysomal aggregation (8).…”