Formation of dopamine quinone-DNA adducts and their potential role in the etiology of Parkinson's disease.
IUBMB Life
; 63(12): 1087-93, 2011 Dec.
Article
en En
| MEDLINE
| ID: mdl-22045657
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Enfermedad de Parkinson
/
Dopamina
/
Monofenol Monooxigenasa
/
Aductos de ADN
/
Antioxidantes
Tipo de estudio:
Etiology_studies
Límite:
Humans
Idioma:
En
Revista:
IUBMB Life
Asunto de la revista:
BIOLOGIA MOLECULAR
/
BIOQUIMICA
Año:
2011
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Reino Unido