Hydroxyl radical formation via iron-mediated Fenton chemistry is inhibited by methylated catechols.
The differing effects of O-methylated catecholamines and their dihydroxyphenyl precursors on the production of *OH were quantified using a previously established specific salicylate hydroxylation assay in conjunction with a sensitive electrochemical detection system. The production of *OH by the Fenton reaction was diminished significantly by O-methylated catecholamines (O-methyldopa, O-methyldopamine, O-methyltyrosine, and N-acetyl-O-methyldopamine), whereas radical production was augmented by dihydroxyphenyls (DOPA, dopamine, and N-acetyldopamine), including those with methylated side chains (N-methyldopamine and alpha-methyldopa). Monohydroxyphenyls such as octopamine, tyramine, tyrosine, and alpha-methyltyrosine had little or no effect on radical production. These data show that a methyl group positioned on the side chain of a catecholamine does not alter its pro-oxidant behavior, while a methyl group positioned on the aromatic ring renders the catecholamine sterically or kinetically unfavorable for coordination with transition metals, thus preventing the promotion of Fenton chemistry. These results highlight the importance of O-methylation in forming catechols that are less reactive than their dihydroxyphenyl precursors. Thus, factors regulating the methylation of brain catecholamines may play a crucial role in mediating neuronal integrity during aging and in the pathogenesis of certain neurodegenerative disorders. Competitive side-chain methylation reactions may sustain or perpetuate some dihydroxyphenyls, creating an oxidatively less favorable environment for cells than would result from compounds formed by O-methylation.
Nappi
A J
AJ
Department of Biology, Loyola University Chicago, IL 60626, USA. anappi@orion.it.luc.edu
Vass
E
E
D000375:Aging / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002394:Catechol O-Methyltransferase / Q000378:metabolism; D002395:Catecholamines / Q000737:chemistry / Q000378:metabolism; D002396:Catechols / Q000737:chemistry* / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004295:Dihydroxyphenylalanine / Q000737:chemistry / Q000378:metabolism; D004298:Dopamine / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D017665:Hydroxyl Radical / Q000737:chemistry* / Q000378:metabolism*; D066298:In Vitro Techniques; D007501:Iron / Q000737:chemistry* / Q000378:metabolism*; D007700:Kinetics; D008745:Methylation; D008956:Models, Chemical; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000378:metabolism
D002395:Catecholamines; D002396:Catechols; D017665:Hydroxyl Radical; D004295:Dihydroxyphenylalanine; D007501:Iron; D002394:Catechol O-Methyltransferase; D004298:Dopamine