title: Impaired transmethylation potential in Parkinson's disease patients treated with L-Dopa.
abstract: Hyperhomocysteinaemia was reported in patients with Parkinson's disease (PD) treated with l-Dopa. The increase in plasma concentration of this sulfur compound arises from the massive methylation of the drug operated by the enzyme catechol-O-methyltransferase (COMT), which acts as a powerful sink of methyl groups. The contemporary occurrence of C677T polymorphism in homozygosity, leading to a temperature-labile variant of the MTHFR enzyme, induces an even more marked increase in tHcy. Here we show that l-Dopa administration in hyperhomocysteinemic PD patients is able to lower intracellular concentration of S-Adenosylmethionine (AdoMet) in erythrocytes (RBC), while the occurrence of hyperhomocysteinaemia causes a significant increase in S-Adenosylhomocysteine (AdoHcy) level. In patients with PD treated with l-Dopa and hyperhomocysteinemic, the remarkable decrease in AdoMet and the concurrent increase in AdoHcy concentration both contribute to significantly lower the transmethylation potential ([AdoMet]/[AdoHcy]), a useful index of the effectiveness of methyl group transfer by methyltransferases. This decrease could indeed contribute to partly attenuate, through a self-limiting kinetic mechanism, the tendency of developing drug resistance, partly mediated in these patients by COMT upregulation. Our results also support the conclusion that COMT inhibitors (entacapone or tolcapone), when administered in PD patients treated with l-Dopa, may potentiate the endogenous AdoHcy-dependent COMT inhibition mechanism already operative in a variable fashion.
authors.affiliation: Department of Biochemistry and Biophysics, Second University of Naples, Italy.
authors.forename: Maria Luigia
authors.initials: ML
authors.lastname: De Bonis
authors.forename: Alessandro
authors.initials: A
authors.lastname: Tessitore
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Pellecchia
authors.forename: Katia
authors.initials: K
authors.lastname: Longo
authors.forename: Anna
authors.initials: A
authors.lastname: Salvatore
authors.forename: Antonio
authors.initials: A
authors.lastname: Russo
authors.forename: Diego
authors.initials: D
authors.lastname: Ingrosso
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Zappia
authors.forename: Paolo
authors.initials: P
authors.lastname: Barone
authors.forename: Patrizia
authors.initials: P
authors.lastname: Galletti
authors.forename: Gioacchino
authors.initials: G
authors.lastname: Tedeschi
mesh_terms: D000368:Aged; D000978:Antiparkinson Agents / Q000494:pharmacology*; D003430:Cross-Sectional Studies; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D005838:Genotype; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D007980:Levodopa / Q000627:therapeutic use*; D008297:Male; D008745:Methylation; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism*; D011110:Polymorphism, Genetic; D012435:S-Adenosylhomocysteine / Q000097:blood; D012436:S-Adenosylmethionine / Q000097:blood
chemical_list: D000978:Antiparkinson Agents; D006710:Homocysteine; D007980:Levodopa; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D042965:Methylenetetrahydrofolate Reductase (NADPH2)