Decrease in liver aromatic L-amino-acid decarboxylase produced by chronic administration of L-dopa.
L-Dopa, an intermediate in the biosynthesis of catecholamines, is now widely used in the treatment of parkinsonism. A number of clinical observations suggested that L-dopa may induce changes in its own metabolism during the course of therapy. In the present study, it was found that when L-dopa was administered to rats, the activity of liver aromatic L-amino-acid decarboxylase, the enzyme which catalyzes the conversion of dopa to dopamine, was reduced by as much as 50%. There were no corresponding changes in enzyme activity in heart, adrenals, kidneys, and brain. Decarboxylase activity in the liver continued to decrease for at least 5 days after the last dose of L-dopa. The reduction of enzyme activity in the liver occurred when L-dopa was administered either subcutaneously or orally at doses comparable to those used clinically. In vitro and in vivo experiments indicated that this action of L-dopa is not due to some effect on the cofactor, pyridoxal phosphate. Immunological evidence was obtained that enzyme protein is reduced in the same proportion as enzyme activity. By a reduction of decarboxylase activity in liver without any affect on the enzyme in brain, more L-dopa should be made available to the brain for decarboxylation to dopamine. These findings may explain the clinical observations that the therapeutic efficacy of the drug increases with continued administration.
D000284:Administration, Oral; D000311:Adrenal Glands / Q000201:enzymology; D000596:Amino Acids; D000818:Animals; D001921:Brain / Q000201:enzymology; D002262:Carboxy-Lyases / Q000032:analysis*; D004295:Dihydroxyphenylalanine / Q000008:administration & dosage / Q000494:pharmacology*; D004789:Enzyme Activation; D005260:Female; D007118:Immunoassay; D007279:Injections, Subcutaneous; D007668:Kidney / Q000201:enzymology; D008099:Liver / Q000201:enzymology*; D009206:Myocardium / Q000201:enzymology; D011732:Pyridoxal Phosphate / Q000494:pharmacology; D051381:Rats; D013997:Time Factors
D000596:Amino Acids; D011732:Pyridoxal Phosphate; D004295:Dihydroxyphenylalanine; D002262:Carboxy-Lyases