The metabolism of m-tyrosine.

Abstract

The development of a method for the large scale synthesis and resolution of m-hydroxyphenylalanine (hereafter referred to as m-tyrosine for convenience) led to investigation of the biological differences between the optically pure isomers of this compound. Aspects of the biosynthesis, pharmacological actions, and metabolism of m-hydroxyphenyl compounds were studied using the rat as an experimental model. The suggestion that m-hydroxyphenyl amines are responsible for the behavioral effects of m-tyrosine was tested. The activity of rats showed significant increases after L-m-tyrosine administration. The inhibition of dopa decarboxylase prevented this hyperactivity while the inhibition of monoamine oxidase potentiated it. m-Tyrosine could also reverse reserpine akinesia for a short period, lending support to speculations that m-hydroxyphenyl amines can mimic the actions of catecholamines. A biochemical basis was then advanced for the effects of m-tyrosine. Its ability to deplete endogenous amine stores in the brain was confirmed and studied in detail. Levels of norepinephrine, dopamine, and serotonin fell 50% one hour after administration of 150 mg/kg L-m-tyrosine. D-m-tyrosine was less potent in effecting the depletion than the L-isomer under all experimental conditions. The inhibition of dopa decarboxylase resulted in less m-hydroxyphenyl amine formation in the brain in vivo, and this was correlated with a reduction in the degree of depletion of brain monoamines. The mechanism of depletion was further examined using brain homogenates. While m-tyrosine does not interfere with the exchange of biogenic amines in this tissue fraction, m-tyramine does displace the endogenous amines. Considerable evidence was thus obtained in support of the hypothesis that both the hyperactivity and depletion of endogenous amines observed after m-tyrosine administration is due to the action of m-hydroxyphenyl amines produced by the in vivo decarboxylation of the amino acid. (Abstract shortened by UMI.)