m-FLUOROTYROSINE CONVULSIONS AND MORTALITY: RELATIONSHIP TO CATECHOLAMINE AND CITRATE METABOLISM

¹ Department of Pharmacology, Chas. Pfizer and Company, Inc., Groton, Connecticut

The characteristic convulsions and mortality induced by DL-m-fluorotyrosine (m-FT), in mice were antagonized by anticonvulsant drugs, but not by high doses of chlorpromazinc, atropine, lysergic acid diethylamide or several drugs variously affecting catecholamine metabolism or storage. Sublethal doses of m-FT were slightly potentiated by -methyltyrosine and by catecholamine depletors, but these effects were marginal and a variety of other centrally acting drugs was ineffective in potentiating m-FT. Despite the structural similarity of m-FT to several potent tyrosine hydroxylase inhibitors, m-FT was essentially inactive as a tyrosine hydroxylase inhibitor in vitro; similarly, m-FT only slightly reduced norepinephrine concentrations in mouse brain. m-FT did, however, cause pronounced accumulation of citric acid in mouse kidney and brain. It is postulated that the convuLsions and mortality caused by m-FT are primarily unrelated to catecholamine metabolism, but are instead the result of metabolism of m-FT through tyrosine pathways to fluoroacetate. Supporting evidence was provided by a study of o-, m- and p-fluorophenylalanine; only the m isomer was lethal at low doses, and only this compound caused citric acid accumulation, The speculative explanation that m-FT is toxic by being metabolized to fluoroacetate does not, however, explain why in mice m-FT has more convulsant properties and is more toxic than fluoroacetate, its proposed active metabolite; drug penetration factors may account for these discrepancies

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