Journal Article

Catechol ortho-quinones: the electrophilic compounds that form depurinating DNA adducts and could initiate cancer and other diseases

Ercole L. Cavalieri, Kai-Ming Li, Narayanan Balu, Muhammad Saeed, Prabu Devanesan, Sheila Higginbotham, John Zhao, Michael L. Gross and Eleanor G. Rogan

in Carcinogenesis

Volume 23, issue 6, pages 1071-1077
Published in print June 2002 | ISSN: 0143-3334
Published online June 2002 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/23.6.1071
Catechol ortho-quinones: the electrophilic compounds that form depurinating DNA adducts and could initiate cancer and other diseases

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Catechol estrogens and catecholamines are metabolized to quinones, and the metabolite catechol (1,2-dihydroxybenzene) of the leukemogenic benzene can also be oxidized to its quinone. We report here that quinones obtained by enzymatic oxidation of catechol and dopamine with horseradish peroxidase, tyrosinase or phenobarbital-induced rat liver microsomes react with DNA by 1,4-Michael addition to form predominantly depurinating adducts at the N-7 of guanine and the N-3 of adenine. These adducts are analogous to the ones formed with DNA by enzymatically oxidized 4-catechol estrogens (Cavalieri,E.L., et al. (1997) Proc. Natl Acad. Sci., 94, 10937). The adducts were identified by comparison with standard adducts synthesized by reaction of catechol quinone or dopamine quinone with deoxyguanosine or adenine. We hypothesize that mutations induced by apurinic sites, generated by the depurinating adducts, may initiate cancer by benzene and estrogens, and some neurodegenerative diseases (e.g. Parkinson's disease) by dopamine. These data suggest that there is a unifying molecular mechanism, namely, formation of specific depurinating DNA adducts at the N-7 of guanine and N-3 of adenine, that could initiate many cancers and neurodegenerative diseases.

Keywords: Ade, adenine; o-BQ, ortho-benzoquinone; CAT, catechol or 1,2-dihydroxybenzene; CE, catechol estrogen(s); CE-Q, catechol estrogen quinone(s); COMT, catechol-O-methyltransferase; DA, dopamine; dG, deoxyguanosine; DMF, dimethylformamide; E1, estrone; E2, estradiol; E1(E2)-3,4-Q, estrone(estradiol)-3,4-quinones or catechol estrogen-3,4-quinones; FAB, fast atom bombardment; Gua, guanine; MS/MS, tandem mass spectrometry; NADA, N-acetyldopamine; OHE1(E2), hydroxyestrone(estradiol); TFA, trifluoroacetic acid.

Journal Article.  6367 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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