Abstract

The administration of L-dopa for several days has been shown to result in decreased activity in vitro of the catecholamine biosynthetic enzymes in peripheral tissues, but not in the brain. Decreased tyrosine hydroxylase activity has been demonstrated to occur in adrenals, heart and the vasculature, while the decrease in aromatic L-amino acid decarboxylase seems to be confined to the liver. In both cases, the decreased enzyme activity appears to be due to diminished levels of enzyme protein. In the case of tyrosine hydroxylase, no evidence could be found for the presence of inhibitors or the removal of activators after L-dopa administration nor were the kinetic properties of the enzyme altered. Immunological titration of the liver decarboxylase with a monospecific antiserum to aromatic L-amino acid decarboxylase indicated an actual decrease in enzyme protein, which corresponded to the decrease in enzyme activity observed after L-dopa administration.

The specific decrease in liver decarboxylase without a similar effect in the brain may explain the increased efficacy of L-dopa in the treatment of Parkinson's disease, seen with continued administration of this amino acid. A decreased level of peripheral decarboxylation should make more of the administered L-dopa available for entry into the brain where it may be decarboxylated to dopamine.

The decrease in both tyrosine hydroxylase and aromatic L-amino acid decarboxylase are independent of endocrine factors under the control of the pituitary, since decreases in both these enzymes were observed following L-dopa administration to hypophysectomized animals. The decrease in adrenal tyrosine hydroxylase was not dependent on sympathetic nerve activity, since L-dopa administration diminished enzyme activity in the denervated adrenal gland.

L-Dopa itself does not mediate the decreased levels of tyrosine hydroxylase and aromatic L-amino acid decarboxylase, but rather the catecholamines formed from it appear to be the causative agents. The excess formation of serotonin from administered L-5-hydroxytryptophan also appears to be the causative factor in reducing the liver decarboxylase. The enzyme aromatic L-amino acid decarboxylase is common to both the noradrenergic and serotonergic pathways and is also capable of forming other biologically active amines, such as tryptamine, phenylethylamine, etc. (9). It is possible that the presence of any of these amines in excess may have a regulatory effect on liver aromatic L-amino acid decarboxylase similar to that produced by the catecholamines and serotonin.

The effects on tyrosine hydroxylase and aromatic L-amino acid decarboxylase, as well as those on dopamine-β-hydroxylase (24) and monoamine oxidase (45), may be viewed as adaptive mechanisms in response to the overproduction of biogemc amines. It is possible that the elaboration of large amounts of these substances, such as occurs in patients with pheochromocytoma or carcinoid, may profoundly influence the tissue levels of their biosynthetic and degradative enzymes.

A number of amino acids capable of forming biologically active amines are now in use as therapeutic agents. Examples would include L-dopa in Parkinson's disease, α-methyldopa in hypertension and 5-hydroxytryptophan for the experimental treatment of depression. These compounds are usually given chronically. Physicians who treat their patients with these drugs should be aware of the possibility of inducing changes in the enzyme systems involved in the catecholamine and serotonin pathways.