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

Muhammad Zahid, Muhammad Saeed, Li Yang, Cheryl Beseler, Eleanor Rogan, Ercole L. Cavalieri

Research output: Contribution to journalArticle

23 Scopus citations

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-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.

Original languageEnglish (US)
Pages (from-to)1087-1093
Number of pages7
JournalIUBMB Life
Volume63
Issue number12
DOIs
StatePublished - Dec 2011

Keywords

  • 1,4-Michael addition
  • Depurinating dopamine-DNA adducts
  • Dopamine quinone
  • Prevention of dopamine-DNA adduct formation
  • Tyrosinase-activated dopamine

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics
  • Clinical Biochemistry
  • Cell Biology

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