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Nucleic Acids Research 2005 33(11):3513-3520; doi:10.1093/nar/gki661
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Published online 21 June 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oupjournals.org

Article

Polyamines stimulate the formation of mutagenic 1,N2-propanodeoxyguanosine adducts from acetaldehyde

Jacob A. Theruvathu, Pawel Jaruga1,2, Raghu G. Nath, Miral Dizdaroglu1 and P. J. Brooks*

Section on Molecular Neurobiology, Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH 5625 Fishers Lane, Room 3S32, MSC 9412, Bethesda, MD 20952-9412, USA 1Chemical Science and Technology Laboratory, National Institute of Standards and Technology Bldg 227, Room A243, MS 8311 Gaithersburg, MD 20899-8311, USA 2Department of Chemical and Biochemical Engineering, University of Maryland Baltimore Country Balitmore, MD 22777, USA

*To whom correspondence should be addressed. Tel: +1 301 496 7920; Fax: +1 301 480 2839; Email: pjbrooks{at}mail.nih.gov

Received April 18, 2005. Revised May 28, 2005. Accepted May 28, 2005.

Alcoholic beverage consumption is associated with an increased risk of upper gastrointestinal cancer. Acetaldehyde (AA), the first metabolite of ethanol, is a suspected human carcinogen, but the molecular mechanisms underlying AA carcinogenicity are unclear. In this work, we tested the hypothesis that polyamines could facilitate the formation of mutagenic {alpha}-methyl-{gamma}-hydroxy-1,N2-propano-2'-deoxyguanosine (Cr-PdG) adducts from biologically relevant AA concentrations. We found that Cr-PdG adducts could be formed by reacting deoxyguanosine with µM concentrations of AA in the presence of spermidine, but not with either AA or spermidine alone. The identities of the Cr-PdG adducts were confirmed by both liquid and gas chromatography-mass spectrometry. Using a novel isotope-dilution liquid chromatography-mass spectrometry assay, we found that in the presence of 5 mM spermidine, AA concentrations of 100 µM and above resulted in the formation of Cr-PdG in genomic DNA. These AA levels are within the range that occurs in human saliva after alcoholic beverage consumption. We also showed that spermidine directly reacts with AA to generate crotonaldehyde (CrA), most likely via an enamine aldol condensation mechanism. We propose that AA derived from ethanol metabolism is converted to CrA by polyamines in dividing cells, forming Cr-PdG adducts, which may be responsible for the carcinogenicity of alcoholic beverage consumption.

Present address: Raghu G. Nath, Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Road NW, Washington, DC 20057, USA


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T.-F. Cheng, X. Hu, A. Gnatt, and P. J. Brooks
Differential Blocking Effects of the Acetaldehyde-derived DNA Lesion N2-Ethyl-2'-deoxyguanosine on Transcription by Multisubunit and Single Subunit RNA Polymerases
J. Biol. Chem., October 10, 2008; 283(41): 27820 - 27828.
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