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dl ‐[2‐ 14 C] p ‐CHLOROPHENYLALANINE AS AN INHIBITOR OF TRYPTOPHAN 5‐HYDROXYLASE
Author(s) -
Gál E. M.,
Roggeveen A. E.,
Millard S. A.
Publication year - 1970
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1970.tb03372.x
Subject(s) - phenylalanine hydroxylase , phenylalanine , tryptophan , in vivo , transamination , tyrosine hydroxylase , tryptophan hydroxylase , chemistry , metabolite , enzyme , tyrosine , biochemistry , incubation , amino acid , endocrinology , medicine , serotonin , biology , receptor , serotonergic , microbiology and biotechnology
— The distribution in vivo of dl ‐[2‐ 14 C] p ‐chlorophenylalanine ( p ‐CP) in regions and subcellular fractions of the rat brain was determined. The half‐lives of p ‐CP and its metabolite p ‐chlorophenylpyruvic acid ( p ‐CPPA) in plasma and brain were correlated with the development of inhibition of cerebral tryptophan 5‐hydroxylase (EC 1.99.1.4). There was active transamination in vivo of p ‐CP and p ‐CPPA in the brain. Transport of indolealkylamino acids into brain was impaired by p ‐CP. Inhibition of tryptophan 5‐hydroxylase could not be reversed by administration of large doses of l ‐tryptophan, l ‐tyrosine, or l ‐phenylalanine. After administration of [2‐ 14 C] p ‐CP in vivo , appreciable radioactivity was bound to cerebral proteins, including those with tryptophan 5‐hydroxylase activity, as well as to phenylalanine 4‐hydroxylase (EC 1.99.1.2) purified from liver. Amino acid analysis of the acid hydrolysate of purified, radioactive hepatic phenylalanine 4‐hydroxylase showed over 80 per cent of the radioactivity to be present as p ‐CP. Neither the inhibition in vivo nor in vitro of tryptophan 5‐hydroxylase could be reversed by dialysis; in controls, dialysis resulted in marked loss of enzyme activity. After incubation for 5 min with p ‐CP in vitro , enzymic activity was inhibited 60 per cent. In vitro, p ‐CPPA labelled protein much more extensively than p ‐CP, yet inhibited the enzyme less. Some of the label from p ‐CPPA was removable by dialysis.