Effects of p-chlorophenylalanine and α-methylphenylalanine on amino acid uptake and protein synthesis in mouse neuroblastoma cells

Abstract

The phenylalanine analogs p-chlorophenylalanine and .alpha.-methylphenylalanine were used to inhibit phenylalanine hydroxylase in animal models for phenylketonuria. The present report examines the affects of these analogs on the metabolism of neuroblastoma cells. p-Chlorophenylalanine inhibited growth and was toxic to neuroblastoma cells. Although in vivo this analog increased cell monoribosomes by 42%, it did not significantly affect poly(U)-directed protein synthesis in vitro. p-Chlorophenylalanine did not compete with phenylalanine or tyrosine for aminoacylation of tRNA and was not substituted for those amino acids in nascent polypeptides. The initial cellular uptake of various large neutral amino acids was inhibited by this analog but did not affect the flux of amino acids already in the cell. This suggested that an alteration of the cell''s amino acid pools was not responsible for the cytotoxicity of the analogs. With p-chlorophenylalanine, .alpha.-methylphenylalanine did not exert these direct toxic efects because the administration of .alpha.-methylphenylalanine in vivo did not affect brain polyribosomes and a comparable concentration of this analog was neither growth inhibitory nor cytotoxic to neuroblastoma cells in culture. The suitability of each analog as an inhibitor of phenylalanine hydroxylase in animal models for phenylketonuria is discussed.