The long term goal of this research is to understand fundamental and applied aspects of the chemistry of carcinogenic nitrosamines. Nitrosamines are a large class of compounds of varied structure to which there is human exposure through endogenous formation and environmental sources. Most of the nitrosamines investigated are carcinogenic or mutagenic in the Ames test when activated by liver microsomes. Nitrosamines are found in groundwater, foods, personal care products, and tobacco products and are encountered in a number of industrial environs, in particular in rubber manufacturing and curing facilities, metal and leather working concerns. The mechanism by which the simplest nitrosamines manifest their deleterious actions is reasonably well understood. They tend to target the oxygen atoms of DNA. By means of the adducts they form they cause replicative polymerases to mis-insert opposite these lesions leading to mutation. Some fundamental aspects are not well understood - for example why the diazonium ions formed from nitrosamines tend to target the oxygen atoms and why there are mutation/adduct deposition hotspots. This proposal contains experimental approaches by which these issues can finally be resolved. The proposal also seeks to understand the more complex chemistry of a """"""""non-simple"""""""" nitrosamine - N- Nitrosomorpholine (NMOR) - to which there is human exposure. Recent work from this laboratory has demonstrated that a metabolite of NMOR decomposes to give nucleoside adducts of novel structure, ones that contain a pendant aldehyde. These slowly decompose to hydroxyethyl lesions. Such pendant aldehyde adducts are likely widely encountered from sources such as other nitrosamines and the products of DNA oxidation and lipid peroxidation as well as other environmental toxicants. It is intended to understand the damage spectrum derived from the metabolite, how it evolves with time and also to construct the novel adducts in oligonucleotides and to study their structure and cross-linking activities by NMR and trapping studies. The combination of novel technical and synthetic approaches are integrated toward a complete and detailed understanding of fundamental aspects of DNA damage and structures that have broad application.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Etiology Study Section (CE)
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Johnson, Ronald L
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University of Maryland Balt CO Campus
Schools of Arts and Sciences
United States
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Koissi, Niangoran; Fishbein, James C (2013) Trapping of a cross-link formed by a major purine adduct of a metabolite of the carcinogen N-nitrosomorpholine by inorganic and biological reductants. Chem Res Toxicol 26:732-40
Koissi, Niangoran; Shah, Niti H; Ginevan, Brandon et al. (2012) Lactone metabolite common to the carcinogens dioxane, diethylene glycol, and N-nitrosomorpholine: aqueous chemistry and failure to mediate liver carcinogenesis in the F344 rat. Chem Res Toxicol 25:1022-8
Pence, Matthew G; Blans, Patrick; Zink, Charles N et al. (2011) Bypass of Nýý-ethylguanine by human DNA polymerase ýý. DNA Repair (Amst) 10:56-64
Zink, Charles N; Soissons, Nicolas; Fishbein, James C (2010) Products of the direct reaction of the diazonium ion of a metabolite of the carcinogen N-nitrosomorpholine with purines of nucleosides and DNA. Chem Res Toxicol 23:1223-33
Holland, Ryan; Navamal, Mettachit; Velayutham, Murugesan et al. (2009) Hydrogen peroxide is a second messenger in phase 2 enzyme induction by cancer chemopreventive dithiolethiones. Chem Res Toxicol 22:1427-34
Pence, Matthew G; Blans, Patrick; Zink, Charles N et al. (2009) Lesion bypass of N2-ethylguanine by human DNA polymerase iota. J Biol Chem 284:1732-40
Upton, Dana C; Wang, Xueying; Blans, Patrick et al. (2006) Mutagenesis by exocyclic alkylamino purine adducts in Escherichia coli. Mutat Res 599:1-10
Zink, Charles N; Kim, Hyun-Joong; Fishbein, James C (2006) Synthesis and aqueous chemistry of alpha-acetoxy-N-nitrosomorpholine: reactive intermediates and products. J Org Chem 71:202-9
Perrino, Fred W; Harvey, Scott; Blans, Patrick et al. (2005) Polymerization past the N2-isopropylguanine and the N6-isopropyladenine DNA lesions with the translesion synthesis DNA polymerases eta and iota and the replicative DNA polymerase alpha. Chem Res Toxicol 18:1451-61
Blans, Patrick; Fishbein, James C (2004) Determinants of selectivity in alkylation of nucleosides and DNA by secondary diazonium ions: evidence for, and consequences of, a preassociation mechanism. Chem Res Toxicol 17:1531-9

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