A biochemical explanation of phenyl acetate neurotoxicity in experimental phenylketonuria.

The in vivo formation of [1-14C]acetyl-coenzyme A from D-[3-14C]3-hydroxybutyrate in the brain of the suckling rat was not affected by postnatal exposure to phenyl acetate. However, utilization of the generated acetyl-coenzyme A was significantly inhibited in certain metabolic reactions, namely synthesis of fatty acids and of sterols, but not in others as the Krebs cycle reactions that lead to the production of dicarboxylic amino acids. The incorporation of D-[U-14C]glucosamine into N-acetylneuraminic acid bound to glycoproteins was appreciably diminished in the rat pup previously exposed to maternal phenylketonuria induced by phenyl acetate. During the period of very rapid development of the brain, interference by phenyl acetate and/or its metabolites with certain critical biosynthetic pathways that require acetyl-coenzyme A would significantly contribute to retarded maturation of the brain that occurs in phenylketonuria.