New pathway for metabolism of dopa

Abstract

L-DOPA (3, 4-dihydroxyphenylalanine) has, since 1967, been used in large doses clinically to lessen the degree of akinesia, rigidity and tremor in Parkinson's disease¹. The impetus for dopa therapy came from the discovery of abnormally small concentrations of dopamine in the basal ganglia of patients with Parkinsonism². Since catecholamines cannot cross the blood-brain barrier, dopa, the immediate metabolic precursor of dopamine, became the logical candidate for clinical trials. Administration of dopa increases dopamine in the basal ganglia³, and this is believed to be the primary mode of action of the drug. Although partially correct, this cannot account for the so-called on–off effect⁴—the increase in therapeutic benefits derived from prolonged use of dopa⁵—and side effects such as nausea, vomiting and personality disturbances. The latter are minimised by simultaneous administration of decarboxylase inhibitors which limit peripheral decarboxylation and allow smaller doses of dopa to be effective. Nonetheless it seems that the action of dopa is complex, with several mechanisms operative. It is therefore important to elucidate all possible metabolic fates of dopa and consider their relationship to the various effects of dopa. We report here in vitro evidence for a minor pathway of dopa metabolism resulting in the formation of 3,4-dihydroxy-phenylacetaldehyde (DHPA) with concomitant inactivation of dopa decarboxylase.