Formation of dopamine quinone‐DNA adducts and their potential role in the etiology of Parkinson's disease

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‐OHE 1 (E 2 )‐1‐N3Ade] and 4‐OHE 1 (E 2 )‐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. © 2011 IUBMB IUBMB Life, 63(12): 1087–1093, 2011