Abstract.
Exposure to estrogens is a risk factor for breast and other human cancers. Initiation of breast, prostate and other cancers has been hypothesized to result from reaction of specific estrogen metabolites, catechol estrogen-3,4-quinones, with DNA to form depurinating adducts at the N-7 of guanine and N-3 of adenine by 1,4-Michael addition. The catechol of the carcinogenic synthetic estrogen hexestrol, a hydrogenated derivative of diethylstilbestrol, is metabolized to its quinone, which reacts with DNA to form depurinating adducts at the N-7 of guanine and N-3 of adenine. The catecholamine dopamine and the metabolite catechol (1,2-dihydroxybenzene) of the leukemogen benzene can also be oxidized to their quinones, which react with DNA to form predominantly analogous depurinating adducts. Apurinic sites formed by depurinating adducts are converted into tumor-initiating mutations by error-prone repair. These mutations could initiate cancer by estrogens and benzene, and Parkinson's disease by the neurotransmitter dopamine. These data suggest a unifying molecular mechanism of initiation for many cancers and neurodegenerative diseases and lay the groundwork for designing strategies to assess risk and prevent these diseases.
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Received 4 September 2001; received after revision 28 November 2001; accepted 2 December 2001
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Cavalieri, E., Rogan, E. & Chakravarti, D. Initiation of cancer and other diseases by catechol ortho-quinones: a unifying mechanism. CMLS, Cell. Mol. Life Sci. 59, 665–681 (2002). https://doi.org/10.1007/s00018-002-8456-0
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DOI: https://doi.org/10.1007/s00018-002-8456-0