title: Formation of dopamine quinone-DNA adducts and their potential role in the etiology of Parkinson's disease.
abstract: The neurotransmitter dopamine is oxidized to its quinone (DA-Q), which at neutral pH undergoes intramolecular cyclization by 1,4-Michael addition, followed by oxidation to form leukochrome, then aminochrome, and finally neuromelanin. At lower pH, the amino group of DA is partially protonated, allowing the competitive intermolecular 1,4-Michael addition with nucleophiles in DNA to form the depurinating adducts, DA-6-N3Ade and DA-6-N7Gua. Catechol estrogen-3,4-quinones react by 1,4-Michael addition to form the depurinating 4-hydroxyestrone(estradiol)-1-N3Ade [4-OHE1(E2)-1-N3Ade] and 4-OHE1(E2)-1-N7Gua adducts, which are implicated in the initiation of breast and other human cancers. The effect of pH was studied by reacting tyrosinase-activated DA with DNA and measuring the formation of depurinating adducts. The most adducts were formed at pH 4, 5, and 6, and their level was nominal at pH 7 and 8. The N3Ade adduct depurinated instantaneously, but N7Gua had a half-life of 3 H. The slow loss of the N7Gua adduct is analogous to that observed in previous studies of natural and synthetic estrogens. The antioxidants N-acetylcysteine and resveratrol efficiently blocked formation of the DA-DNA adducts. Thus, slightly acidic conditions render competitive the reaction of DA-Q with DNA to form depurinating adducts. We hypothesize that formation of these adducts could lead to mutations that initiate Parkinson's disease. If so, use of N-acetylcysteine and resveratrol as dietary supplements may prevent initiation of this disease.
authors: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE 68198-6805, USA.
authors: Muhammad
authors: M
authors: Zahid
authors: Muhammad
authors: M
authors: Saeed
authors: Li
authors: L
authors: Yang
authors: Cheryl
authors: C
authors: Beseler
authors: Eleanor
authors: E
authors: Rogan
authors: Ercole L
authors: EL
authors: Cavalieri
mesh_terms: D000111:Acetylcysteine / Q000737:chemistry; D000975:Antioxidants / Q000737:chemistry*; D016227:Benzoquinones / Q000737:chemistry / Q000378:metabolism; D018736:DNA Adducts / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D004298:Dopamine / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008550:Melatonin / Q000737:chemistry; D014442:Monophenol Monooxygenase / Q000737:chemistry*; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry; D008063:Thioctic Acid / Q000737:chemistry
chemical_list: D000975:Antioxidants; D016227:Benzoquinones; D018736:DNA Adducts; D013267:Stilbenes; C004532:quinone; D008063:Thioctic Acid; D014442:Monophenol Monooxygenase; D008550:Melatonin; D000077185:Resveratrol; D004298:Dopamine; D000111:Acetylcysteine