Plasma Homocysteine and l-DOPA Metabolism in Patients with Parkinson Disease

Abstract

Homocysteine is formed by demethylation of methionine and is involved in transmethylation mechanisms. Hyperhomocysteinemia is associated with a wide range of clinical manifestations, mostly affecting the central nervous system (e.g., mental retardation, cerebral atrophy, and epileptic seizures) (1)(2). Hyperhomocysteinemia has also been associated with an increased risk for atherosclerotic and thrombotic vascular diseases (3)(4)(5). Although various mechanisms have been proposed, mostly involving endothelial damage related to increased oxidative stress (6), the exact cellular and molecular bases for the adverse effects of homocysteine are still elusive. Alterations in transmethylation reactions that lead to hyperhomocysteinemia have been suggested in the pathophysiology of neurodegenerative disorders such as Alzheimer disease and Parkinson disease (PD) (7)(8). Furthermore, the potential role of homocysteine in neurodegeneration has recently been pointed out by a study showing that the amino acid induces apoptosis in cultures of hippocampal neurons (9). The processes of methyl-group transfer are involved in the metabolism of l-3,4-dihydroxyphenylalanine (l-DOPA), the most effective drug used for the therapy of PD (10). The main metabolism of l-DOPA is its O-methylation to form 3- O -methyldopa (3-OMD). The reaction involves the enzyme catechol- O -methyl-transferase, with S -adenosylmethionine as methyl-group donor. Demethylation of S -adenosylmethionine forms S -adenosylhomocysteine, which is hydrolyzed to homocysteine. Homocysteine is then metabolized via a transsulfuration pathway, forming cystathionine, or a remethylation cycle, which leads back to methionine (11). The catabolism of l-DOPA might therefore interfere, at various steps, with homocysteine metabolism. Indeed, there is experimental evidence that l-DOPA administration increases concentrations of plasma homocysteine (12) and cerebral S -adenosylhomocysteine (12)(13). In PD patients treated with l-DOPA, plasma homocysteine is higher than in controls and untreated PD patients (14)(15)(16)(17). This further supports …