MULTIPLE INHIBITORY EFFECTS OF -METHYLAMIND ACIDS ON THE METABOLISM OF C¹⁴-LABELED TYROSENE, DOPA AND -METHYLDOPA

¹ Allan Memorial Institute, McGill University, Montreal, Canada

A series of "decarboxylase inhibitors" including -methyldopa, -methyl- m-tyrosine and -hydrazino--methyl-3, 4-dihydroxyphenylpropionic acid have been examined for their effects on formation of respiratory C¹⁴ O₂ from intraperitoneally administered C¹⁴-labeled d- and l-tyrosine, d -and dl-dopa, and l--methyldopa. Substantial inhibition of C¹⁴ O₂ expiration after injection of both carboxyl-and labeled tyrosine has been observed in animals receiving -methyldopa, -methyl-m-tyrosine and the hydrazino analogue of a-methyldopa. The results establish the fact that the a-methylamino acids inhibit enzymes on the main pathway of degradation of tyrosine; their inhibitory action cannot be explained simply on the basis of their well-known antidecarboxylase properties. By comparing the effects of the inhibitors on carboxyl-labeled d-and 1-tyrosine it has been shown that the hydrazino analogue of -methyl dopa inhibits l-tyrosine--ketoglutarate transaminase; -methyldopa and -methyl-m-tyrosine inhibit d-amino acid oxidase and, perhaps, also the transaminase or p-hydroxyphenylpyruvate oxidase (or both).

Inhibition of d-amino acid oxidase by -methyldopa, -methyl-m-tyrosine and -meth-ylmethionine was also observed in experiments with d-and dl-dopa labeled in the carboxyl group. However, the hydrazino compound inhibited the two forms of dopa to the same extent; this result has been discussed in relation to the metabolic fate of 3, 4-dihydroxyphenylpyruvic acid, the presumed first intermediate in the catabolism of d-dopa.

-Methyldopa, -methyl-m-tyrosine, -hydrazino--methyl-3, 4-dihydroxyphenyipropionic acid, -methyl-5-hydroxytryptophan, and 5-(3-hydroxycinnamoyl) salicylic acid are effective in inhibiting C¹⁴ O₂ formation from carboxyllabeled dl-dopa and l-methyldopa, thus confirming their "antidecarboxylase" action. However, in experiments utilizing carboxyl-labeled l-tyrosine, -methyl-5-hydroxytryptophan and the salicylic acid derivative did not inhibit the formation of respiratory C¹⁴O₂. It has thus been shown that by the judicious choice of substrate and its labeling in this type of experiment, the specificity of action of the "antidecarboxylases" can be determined in vivo and their other sites of action elucidated.