Initiation of cancer and other diseases by catechol ortho-quinones: a unifying mechanism.
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.
Cavalieri
E L
EL
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha 68198-6805, USA. ecavalie@unmc.edu
Rogan
E G
EG
Chakravarti
D
D
D000818:Animals; D001483:Base Sequence; D001943:Breast Neoplasms / Q000139:chemically induced; D006224:Cricetinae; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism; D004260:DNA Repair; D004967:Estrogens / Q000737:chemistry / Q000378:metabolism; D002393:Estrogens, Catechol / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D005260:Female; D006801:Humans; D051379:Mice; D008957:Models, Genetic; D009153:Mutagens / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D009369:Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000139:chemically induced; D011809:Quinones / Q000737:chemistry / Q000378:metabolism; D011960:Receptors, Estrogen / Q000502:physiology
D018736:DNA Adducts; D004967:Estrogens; D002393:Estrogens, Catechol; D009153:Mutagens; D011809:Quinones; D011960:Receptors, Estrogen