A unifying mechanism in the initiation of cancer and other diseases by catechol quinones.
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.
Cavalieri
Ercole L
EL
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE 68198-6805, USA. ecavalie@unmc.edu
Rogan
Eleanor G
EG
D000818:Animals; D001554:Benzene; D001943:Breast Neoplasms / Q000473:pathology; D002273:Carcinogens; D002396:Catechols / Q000737:chemistry*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D018736:DNA Adducts / Q000737:chemistry; D004298:Dopamine / Q000737:chemistry; D004967:Estrogens / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006838:Hydrocarbons / Q000737:chemistry; D008956:Models, Chemical; D016296:Mutagenesis; D009154:Mutation; D009369:Neoplasms / Q000139:chemically induced / Q000209:etiology / Q000473:pathology*; D010100:Oxygen / Q000737:chemistry / Q000378:metabolism; D011809:Quinones / Q000737:chemistry*
D002273:Carcinogens; D002396:Catechols; D018736:DNA Adducts; D004967:Estrogens; D006838:Hydrocarbons; D011809:Quinones; D004247:DNA; D001554:Benzene; D010100:Oxygen; D004298:Dopamine