Abstract
A series of "decarboxylase inhibitors" including α-methyldopa, α-methyl- m-tyrosine and α-hydrazino-α-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-α-methyldopa. Substantial inhibition of C14 O2 expiration after injection of both carboxyl-and β labeled tyrosine has been observed in animals receiving α-methyldopa, α-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 α-methyl dopa inhibits l-tyrosine-α-ketoglutarate transaminase; α-methyldopa and α-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 α-methyldopa, α-methyl-m-tyrosine and α-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.
α-Methyldopa, α-methyl-m-tyrosine, α-hydrazino-α-methyl-3, 4-dihydroxyphenyipropionic acid, α-methyl-5-hydroxytryptophan, and 5-(3-hydroxycinnamoyl) salicylic acid are effective in inhibiting C14 O2 formation from carboxyllabeled dl-dopa and lα-methyldopa, thus confirming their "antidecarboxylase" action. However, in experiments utilizing carboxyl-labeled l-tyrosine, α-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.
Footnotes
- Accepted January 12, 1965.
- The Williams & Wilkins Comapny
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|