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Journal of Pharmacology And Experimental Therapeutics, Vol. 157, Issue 3, 565-573, 1967
Copyright © 1967 by American Society for Pharmacology and Experimental Therapeutics

DEPENDENCE OF m-FLUOROPHENYLALANINE TOXICITY ON PHENYLALANINE HYDROXYLASE ACTIVITY

B. Kenneth Koe 1 and Albert Weissman 1

1 Department of Pharmacology, Medical Research Laboratories, Chas. Pfizer & Co., Inc., Groton, Connecticut

The potent convulsant and lethal effects exerted by m-fluorophenylalanine (m-FPhe) were antagonized in rats by phenylalanine hydroxylase inhibitors such as p-chlorophenylalanine, agr,beta,beta-trimethyl-dopa and p-fluorophenylalanine. Pretreatment with these compounds, especially p-chlorophenylalanine, markedly increased the latency of convulsion and the survival time obtained with m-FPhe administration. The characteristic accumulation of citric acid in brain and kidney elicited by m-FPhe was also strongly blocked by the phenylalanine hydroxylase inhibitors. These results indicate that poisoning by m-FPhe is dependent on the phenylalanine-hydroxylating system, which probably converts m-FPhe to the toxic amino acid, m-fluorotyrosine (m-FTyr). In support of this conclusion the phenylalanine hydroxylase inhibitors did not appreciably antagonize the toxic and citric acid-accumulating properties of either m-FTyr or sodium fluoroacetate. The correspondence of antagonism of pharmacologic effects with a blockade of phenylalanine hydroxylase activity in liver was imperfect. Some discrepancies were discerned between extent of enzyme inhibition, blockade of citric acid accumulation in tissues induced by m-FPhe and increase in survival time after m-FPhe treatment. Although survival time after a lethal dose of m-FPhe was markedly prolonged by the inhibitors, the protective effect was temporary; characteristic convulsant symptoms and death eventually occurred. The facile demonstration of the blockade of phenylalanine hydroxylase in vivo by comparing the toxic endpoints of substrate and product, as is possible with the m-FPhe and m-FTyr pair, may find application in the in vivo study of this and other enzymatic steps in the tyrosine transaminase pathway.

Submitted on January 9, 1967
Accepted on May 2, 1967




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Copyright © 1967 by the American Society for Pharmacology and Experimental Therapeutics.