A unifying mechanism in the initiation of cancer and other diseases by catechol quinones.

Abstract:

:The first step in cancer initiation is the reaction of chemical carcinogens with DNA to form stable adducts, which remain in DNA unless removed by repair, and depurinating adducts, which detach from DNA following destabilization of the glycosyl bond. Depurinating DNA adducts of polycyclic aromatic hydrocarbons play a major role in the initiation of cancer, as shown by the correlation between depurinating adducts and oncogenic mutations of the H-ras oncogene in mouse skin. Following these results, experiments on the metabolism of estrogens, formation of depurinating DNA adducts, carcinogenicity, mutagenicity, and cellular transformation have led us to the hypothesis that certain metabolites of endogenous estrogens--in particular, estradiol(estrone)-3,4-quinones--can react with DNA to form depurinating adducts at the N-3 of Ade and the N-7 of Gua. Depurination of these adducts can generate critical mutations by error-prone repair to initiate breast, prostate, and other cancers. The oxidation mechanism of catechols to quinone compounds includes not only natural estrogens, but also synthetic estrogens, such as hexestrol and the human carcinogen diethylstilbestrol, which react with DNA to form N3Ade and N7Gua adducts, presumably to initiate cancer. Furthermore, the initiating mechanism of the leukemogen benzene involves oxidation of catechol to catechol quinone, which reacts with DNA to form N3Ade and N7Gua adducts. The quinone of the neurotransmitter dopamine can also react with DNA to form N3Ade and N7Gua adducts. The subsequent mutations could be at the origin of Parkinson's and other neurodegenerative diseases. In summary, the apurinic sites produced in DNA from the loss of these depurinating adducts can be converted into mutations by error-prone repair, which may initiate cancer and other diseases.

journal_name

Ann N Y Acad Sci

authors

Cavalieri EL,Rogan EG

doi

10.1196/annals.1322.029

subject

Has Abstract

pub_date

2004-12-01 00:00:00

pages

247-57

eissn

0077-8923

issn

1749-6632

pii

1028/1/247

journal_volume

1028

pub_type

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