BIOCHEMICAL MEDICINE 12, 72-78 ( 1975) In Vivo Inhibition of Rat Liver Phenylalanine Hydroxylase by p-Chlorophenylalanine and Esculin Experimental Model of Phenylketonuria FERNANDO VALDIVIESO, CECILIO GIMENEZ, AND FEDERICO MAYOR Centro de Investigacih de Alteraciones Mole&ares y Cromosomicas, Departamento de Bioquimica y Biologia Moiecutar, Fact&ad de Ciencias, Universidad Autdnoma de Madrid, Cantobhco, Madrid (Spain) Received July 22. 1974 The phenylalanine hydroxylase system which is responsible for the conversion of phenylalanine (Phe) to tyrosine (Tyr), contains two en- zymes, phenylalanine hydroxylase and dihydropteridine reductase (Scheme 1). The genetically linked lack of the liver phenylalanine 4- hydroxylase activity (EC 1.14.16.1) is the basic biochemical defect in the human error of metabolism “phenylketonuria” (PKU) (1). The ab- sence of this activity leads to an enhancement of the Phe concentration and consequently to the increase or appearance of some of its metabolic derivatives in the tissues and fluids of PKU patients. Koe and Weissman (2) demonstrated that the in viva administration of p-chlorophenylalanine (p-CPA) markedly inhibits the liver phenylal- anine hydroxylase activity. Lipton et al. (3) proposed the use of this Escul in NADP<+)ADPH~.H+ ;:HL< ’ ------hH 0 I,/ ‘_j2D Phenylalanine Tyrosine p-CPA SCHEME 1. Phenylalanine hydroxylase system. p-CPA and esculin inhibit the phenylal- anine hydroxylase (1) and the dihydropteridine reductase (2), respectively. XH, and XH, are the reduced and oxidized forms of the biopterine. 72 Copyright @I 1975 by Academic Press, Inc. Printed in the United States. All rights of reproduction in any form reserved.