title: Oxidatively generated DNA damage after Cu(II) catalysis of dopamine and related catecholamine neurotransmitters and neurotoxins: Role of reactive oxygen species.
abstract: There is increasing evidence supporting a causal role for oxidatively damaged DNA in neurodegeneration during the natural aging process and in neurodegenerative diseases such as Parkinson and Alzheimer. The presence of redox-active catecholamine neurotransmitters coupled with the localization of catalytic copper to DNA suggests a plausible role for these agents in the induction of oxidatively generated DNA damage. In this study we have investigated the role of Cu(II)-catalyzed oxidation of several catecholamine neurotransmitters and related neurotoxins in inducing oxidatively generated DNA damage. Autoxidation of all catechol neurotransmitters and related congeners tested resulted in the formation of nearly a dozen oxidation DNA products resulting in a decomposition pattern that was essentially identical for all agents tested. The presence of Cu(II), and to a lesser extent Fe(III), had no effect on the decomposition pattern but substantially enhanced the DNA product levels by up to 75-fold, with dopamine producing the highest levels of unidentified oxidation DNA products (383±46 adducts/10(6) nucleotides), nearly 3-fold greater than 8-oxo-7,8-dihydro-2'-deoxyguanosine (122±19 adducts/10(6) nucleotides) under the same conditions. The addition of sodium azide, 2,2,6,6-tetramethyl-4-piperidone, tiron, catalase, bathocuproine, or methional to the dopamine/Cu(II) reaction mixture resulted in a substantial decrease (>90%) in oxidation DNA product levels, indicating a role for singlet oxygen, superoxide, H(2)O(2), Cu(I), and Cu(I)OOH in their formation. Whereas the addition of N-tert-butyl-α-phenylnitrone significantly decreased (67%) dopamine-mediated oxidatively damaged DNA, three other hydroxyl radical scavengers, ascorbic acid, sodium benzoate, and mannitol, had little to no effect on these oxidation DNA product levels, suggesting that free hydroxyl radicals may have limited involvement in this dopamine/Cu(II)-mediated oxidatively generated DNA damage. These studies suggest a possible contributory role of oxidatively generated DNA damage by dopamine and related catechol neurotransmitters/neurotoxins in neurodegeneration and cell death. We also found that a naturally occurring broad-spectrum antioxidant, ellagic acid, was substantially effective (nearly 50% inhibition) at low doses (1μM) at preventing this dopamine/Cu(II)-mediated oxidatively generated DNA damage. Because dietary ellagic acid has been found to reduce oxidative stress in rat brains, a neuroprotective role of this polyphenol is plausible.
authors.affiliation: James Graham Brown Cancer Center, Louisville, KY 40202, USA.
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Spencer
authors.forename: Jeyaprakash
authors.initials: J
authors.lastname: Jeyabalan
authors.forename: Sunita
authors.initials: S
authors.lastname: Kichambre
authors.forename: Ramesh C
authors.initials: RC
authors.lastname: Gupta
mesh_terms: D000818:Animals; D002384:Catalysis / Q000187:drug effects; D002395:Catecholamines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D003300:Copper / Q000494:pharmacology*; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D018736:DNA Adducts / Q000032:analysis / Q000378:metabolism; D004249:DNA Damage / Q000502:physiology; D004298:Dopamine / Q000378:metabolism* / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008954:Models, Biological; D009498:Neurotoxins / Q000378:metabolism* / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000378:metabolism* / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000494:pharmacology*; D012474:Salmon / Q000235:genetics; D013737:Testis / Q000378:metabolism
chemical_list: D002395:Catecholamines; D018736:DNA Adducts; D009498:Neurotoxins; D018377:Neurotransmitter Agents; D017382:Reactive Oxygen Species; D003300:Copper; D004247:DNA; D004298:Dopamine