title: Mechanism of DNA depurination by carcinogens in relation to cancer initiation.
abstract: Depurinating DNA adducts formed by aromatic hydrocarbons and catechol estrogen quinones play a major role in cancer initiation. Most of these adducts depurinate instantaneously, but some guanine adducts depurinate from DNA with half-lives of hours. We report here, that after 10 h at 37 °C, reaction of estradiol-3,4-quinone (E(2)-3,4-Q) with ds-DNA to yield N7Gua and N3Ade adducts was complete and more efficient than with ss-DNA. When E(2)-3,4-Q reacted with t-RNA, no adducts were detected after 10 h, and the level of N3Ade and N7Gua adducts after 10 days was less than half that with ss-DNA after 10 h. Reaction of E(2)-3,4-Q and dG yielded 4-OHE(2)-1-N7dG, which spontaneously depurinated to yield 4-OHE(2)-1-N7Gua. To investigate the mechanism of depurination, E(2)-3,4-Q was reacted with carbocyclicdeoxyguanosine, in which the ring oxygen of the deoxyribose moiety is substituted with CH(2) , and depurination was observed. The results from this experiment demonstrate that the oxocarbenium ion mechanism plays the major role in depurination and provides the first experimental evidence for this mechanism. A newly discovered β-elimination mechanism also plays a minor role in depurination. Understanding why the depurinating estrogen-DNA adducts come from DNA, and not from RNA, underscores the critical role that these adducts play in initiating cancer.
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-6805, USA. ecavalie@unmc.edu
authors.forename: Ercole
authors.initials: E
authors.lastname: Cavalieri
authors.forename: Muhammad
authors.initials: M
authors.lastname: Saeed
authors.forename: Muhammad
authors.initials: M
authors.lastname: Zahid
authors.forename: David
authors.initials: D
authors.lastname: Cassada
authors.forename: Daniel
authors.initials: D
authors.lastname: Snow
authors.forename: Momcilo
authors.initials: M
authors.lastname: Miljkovic
authors.forename: Eleanor
authors.initials: E
authors.lastname: Rogan
mesh_terms: D002273:Carcinogens / Q000737:chemistry*; D002471:Cell Transformation, Neoplastic; D003517:Cyclopentanes / Q000737:chemistry; D018736:DNA Adducts / Q000138:chemical synthesis / Q000737:chemistry*; D004249:DNA Damage; D004277:DNA, Single-Stranded / Q000737:chemistry; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000737:chemistry; D004958:Estradiol / Q000031:analogs & derivatives* / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D011687:Purines / Q000737:chemistry; D012343:RNA, Transfer / Q000737:chemistry
chemical_list: D002273:Carcinogens; D003517:Cyclopentanes; D018736:DNA Adducts; D004277:DNA, Single-Stranded; D011687:Purines; C500988:estradiol-3,4-quinone; D004958:Estradiol; D012343:RNA, Transfer; D003849:Deoxyguanosine