Catechol ortho-quinones: the electrophilic compounds that form depurinating DNA adducts and could initiate cancer and other diseases.
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.
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
Li
Kai-Ming
KM
Balu
Narayanan
N
Saeed
Muhammad
M
Devanesan
Prabu
P
Higginbotham
Sheila
S
Zhao
John
J
Gross
Michael L
ML
Rogan
Eleanor G
EG
D001080:Apurinic Acid / Q000378:metabolism*; D002273:Carcinogens / Q000633:toxicity*; D002396:Catechols / Q000633:toxicity*; D018736:DNA Adducts; D004298:Dopamine / Q000494:pharmacology; D002393:Estrogens, Catechol / Q000633:toxicity; D006735:Horseradish Peroxidase / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D014442:Monophenol Monooxygenase / Q000378:metabolism; D009369:Neoplasms / Q000139:chemically induced*; D010634:Phenobarbital / Q000494:pharmacology; D011809:Quinones / Q000633:toxicity*; D014466:Ultraviolet Rays
D002273:Carcinogens; D002396:Catechols; D018736:DNA Adducts; D002393:Estrogens, Catechol; D011809:Quinones; D001080:Apurinic Acid; D006735:Horseradish Peroxidase; D014442:Monophenol Monooxygenase; D004298:Dopamine; D010634:Phenobarbital