Mechanism of DNA depurination by carcinogens in relation to cancer initiation

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 degrees C, reaction of estradiol-3,4-quinone (E2-3,4-Q) with ds-DNA to yield N7Gua and N3Ade adducts was complete and more efficient than with ss-DNA. When E2-3,4-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 E2-3,4-Q and dG yielded 4-OHE2-1-N7dG, which spontaneously depurinated to yield 4-OHE2-1-N7Gua. To investigate the mechanism of depurination, E2-3,4-Q was reacted with carbocyclicdeoxyguanosine, in which the ring oxygen of the deoxyribose moiety is substituted with CH2, 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 beta-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. (c) 2011 IUBMB IUBMB Life, 2011.