title: Inhibition of brain mitochondrial respiration by dopamine and its metabolites: implications for Parkinson's disease and catecholamine-associated diseases.
abstract: A structure-potency study examining the ability of dopamine (DA), its major metabolites and related amine and acetate congeners to inhibit NADH-linked mitochondrial O(2) consumption was carried out to elucidate mechanisms by which DA could induce mitochondrial dysfunction. In the amine studies, DA was the most potent inhibitor of respiration (IC(50) 7.0 mm) compared with 3-methoxytryramine (3-MT, IC(50) 19.6 mm), 3,4-dimethoxyphenylethylamine (IC(50) 28.6 mm), tyramine (IC(50) 40.3 mm) and phenylethylamine (IC(50) 58.7 mm). Addition of monoamine oxidase (MAO) inhibitors afforded nearly complete protection against inhibition by phenylethylamine, tyramine and 3,4-dimethoxyphenylethylamine, indicating that inhibition arose from MAO-mediated pathways. In contrast, the inhibitory effects of DA and 3-MT were only partially prevented by MAO blockade, suggesting that inhibition might also arise from two-electron catechol oxidation and quinone formation by DA and one-electron oxidation of the 4-hydroxyphenyl group of 3-MT. In the phenylacetate studies, 3,4-dihydroxyphenylacetic acid (DOPAC) was equipotent with DA in inhibiting respiration (IC(50) 7.4 mm), further implicating the catechol reaction as the cause of inhibition. All other carboxylate congeners; phenylacetic acid (IC(50) 13.0 mm), 4-hydroxyphenylacetic acid (IC(50) 12.1 mm), 4-hydroxy-3-methoxyphenylacetic acid (HVA, IC(50) 12.0 mm) and 3,4-dimethoxyphenylacetic acid (IC(50) 10.2 mm), were equipotent respiratory inhibitors and two- to fourfold more potent than their corresponding amine. These latter findings suggest that the phenylacetate ion can also contribute independently to mitochondrial inhibition. In summary, mitochondrial respiration can be inhibited by DA and its metabolites by four distinct MAO-dependent and independent mechanisms.
authors.affiliation: Department of Neurology, Bronx Veterans Medical Center, Bronx, New York, USA.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Gluck
authors.forename: Gail D
authors.initials: GD
authors.lastname: Zeevalk
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000494:pharmacology; D000818:Animals; D001923:Brain Chemistry; D002395:Catecholamines / Q000378:metabolism*; D019069:Cell Respiration / Q000187:drug effects* / Q000502:physiology; D004298:Dopamine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D006719:Homovanillic Acid / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008928:Mitochondria / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D008995:Monoamine Oxidase / Q000187:drug effects; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D010300:Parkinson Disease / Q000378:metabolism*; D010627:Phenethylamines / Q000494:pharmacology; D010648:Phenylacetates / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014439:Tyramine / Q000494:pharmacology
chemical_list: D002395:Catecholamines; D008996:Monoamine Oxidase Inhibitors; D010627:Phenethylamines; D010648:Phenylacetates; D015102:3,4-Dihydroxyphenylacetic Acid; C029261:phenethylamine; D008995:Monoamine Oxidase; C025136:phenylacetic acid; C001746:3-methoxytyramine; D004298:Dopamine; D006719:Homovanillic Acid; D014439:Tyramine