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: Ercole Cavalieri, Muhammad Saeed, Muhammad Zahid, David Cassada, Daniel Snow, Momcilo Miljkovic, Eleanor Rogan
• Journal: IUBMB life (IUBMB Life) Vol. 64 Issue 2 Pg. 169-79 (Feb 2012) ISSN: 1521-6551 [Electronic] England
• PMID: 22162200 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2011 Wiley Periodicals, Inc.

Chemical References

• Carcinogens
• Cyclopentanes
• DNA Adducts
• DNA, Single-Stranded
• Purines
• estradiol-3,4-quinone
• Estradiol
• RNA, Transfer
• Deoxyguanosine

Topics

• Carcinogens (chemistry)
• Cell Transformation, Neoplastic
• Cyclopentanes (chemistry)
• DNA Adducts (chemical synthesis, chemistry)
• DNA Damage
• DNA, Single-Stranded (chemistry)
• Deoxyguanosine (analogs & derivatives, chemistry)
• Estradiol (analogs & derivatives, chemistry)
• Humans
• Hydrogen-Ion Concentration
• Kinetics
• Purines (chemistry)
• RNA, Transfer (chemistry)