The influence of DNA repair pathways on the toxicity and mutagenicity induced by pyridyloxobutylating agents

TOXI 23

Li Li, lixxx505@umn.edu, Division of Environmental Health Sciences and the Cancer Center, University of Minnesota, 420 Delaware ST SE, MMC 806, Minneapolis, MN 55455, Anthony E. Pegg, Department of Cellular and Molecular Physiology, Pennsylvania State University, College of Medicine, Hershey, PA 17033, Yanbin Lao, University of Minnesota Cancer Center, 420 Delaware St SE - MMC 806, Minneapolis, MN 55455, Stephen S. Hecht, Cancer Center, University of Minnesota, MMC 806, 420 Delaware St. SE, Minneapolis, MN 55455, Joyce T. Reardon, Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC 27599, Aziz Sancar, Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7260, Elizabeth V. Wattenberg, Division of Environmental and Occupational Health, University of Minnesota, Mayo Mail Code 807, 420 Delaware St SE, Minneapolis, MN 55455, and Lisa A. Peterson, peter431@umn.edu, Environmental Health Sciences and Cancer Center, University of Minnesota, Mayo Mail Code 806, 420 Delaware St SE, Minneapolis, MN 55455.
The tobacco-specific nitrosamines, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)and N'-nitrosonornicotine (NNN),are possible human carcinogens. Metabolic activation of NNK and NNN produces a pyridyloxobutylating intermediate which can react with DNA to form covalent adducts. We determined the cytotoxic and mutagenic activity of a model pyridyloxobutylating agent, 4-(acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone (NNKOAc) in CHO cell lines that were proficient or deficient in O6-alkylguanine DNA alkyltransferase (AGT), or deficient in both AGT and base excision repair or deficient in both AGT and nucleotide excision repair (NER).In addition, we measured the formation and repair of four pyridyloxobutyl DNA adducts, O6-[4-oxo-4-(3-pyridyl)butyl]guanine (O6-pobG), 7-[4-oxo-4-(3-pyridyl)butyl]guanine (7-pobG), O2-[4-oxo-4-(3-pyridyl)butyl]cytidine (O2-pobC) and O2-[4-oxo-4-(3-pyridyl)butyl]thymidine (O2-pobT). The results suggest that O6-pobG is predominantly repaired by AGT. NER is involved in the repair of O2-pobT and possibly O2-pobC and O6-pobG. The repair of these adducts by AGT, NER and BER affects the toxicity and/or mutagenicity of NNKOAc in these cell lines.
 

Young Investigator Session
8:15 AM-12:00 PM, Monday, August 20, 2007 BCEC -- 258C, Oral

Division of Chemical Toxicology

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007