Prooxidant activity of free radicals derived from phenol-containing neurotransmitters.
It has been suggested that biogenic amines may partake in neurodegenerative disease processes by causing oxidative stress. In the following, we present evidence showing for the first time that biogenic amines can form prooxidant radicals when metabolized. The order of prooxidant activity of neurotransmitter phenols or hydroxyindoles in catalyzing beta-nicontinamide adenine dinucleotide (reduced) (NADH) or cysteine cooxidation found when metabolically activated by peroxidase/H(2)O(2) was tyramine>N-acetyltyrosine>tyrosine>serotonin>N-acetylserotonin, 5-hydroxyindoleacetic acid (5-HIAA). This order likely reflects the reactivity of the phenoxyl radicals (for phenols) as extensive oxygen activation accompanied the NADH oxidation and only catalytic amounts of H(2)O(2) were required. The low reactivity of the hydroxyindoles suggests that the redox potential of the radical (semiquinone-imine radical?) was too low to oxidize NADH and/or that the radical dimerization rate was too rapid. The order of catalytic effectiveness for phenolic or hydroxyindole neurotransmitters in catalyzing ascorbate cooxidation on the otherhand, was N-acetylserotonin>serotonin>5-HIAA>>tyramine>N-acetyltyrosine>tyrosine. The first formed hydroxyindole radical product was likely the active cooxidizing species formed from hydroxyindoles. The order for catecholamine catalytic effectiveness in catalyzing NADH or ascorbate cooxidation rate was N-acetyldopamine>3,4-dihydroxyphenylacetic acid (DOPAC)>dopamine>norepinephrine>(-)-3,4-dihydroxyphenylalanine (L-DOPA)>epinephrine which correlated with the second-order rate constant for the peroxidase/H(2)O(2) catalyzed oxidation of the catecholamines. However, the total amount of NADH oxidized was proportional to the amount of H(2)O(2) added and was not accompanied by oxygen uptake, suggesting that NADH was oxidized by the o-quinone metabolite formed by semiquinone radical disproportionation. These results show that biogenic amines form prooxidant radicals, when metabolized by peroxidase, cooxidize cellular antioxidants (ascorbate, NADH, or cysteine).
Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, 19 Russell St., Toronto, Ontario, Canada M5S 2S2.
Arno G
AG
Siraki
Peter J
PJ
O'Brien
D000975:Antioxidants / Q000378:metabolism; D001205:Ascorbic Acid / Q000378:metabolism; D015306:Biogenic Monoamines / Q000378:metabolism*; D003545:Cysteine / Q000378:metabolism; D005609:Free Radicals; D009243:NAD / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000145:classification / Q000378:metabolism*; D010084:Oxidation-Reduction; D019800:Phenol / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013056:Spectrophotometry, Ultraviolet
D000975:Antioxidants; D015306:Biogenic Monoamines; D005609:Free Radicals; D018377:Neurotransmitter Agents; D017382:Reactive Oxygen Species; D009243:NAD; D019800:Phenol; D003545:Cysteine; D001205:Ascorbic Acid