Colorectal cancer is one of the leading causes of cancer deaths in the United States. Both cooked red meat intake and chronic inflammation/infection play a role in the etiology of colon cancer. During the cooking process, genotoxic heterocyclic amines (HCAs), i.e., 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), are formed which can initiate colon cancer. Colorectal carcinoma incidence in patients with inflammatory bowel disease is 20-fold higher and occurs 20 years earlier than the general population. Findings in patients are paralleled in animal models with persistent severe inflammation in the colonic mucosa thought to cause development of colorectal cancer. Dextran sulfate sodium (DSS)-induced colitis is an animal model for studying both inflammation and colitis-associated neoplasia. Reactive nitrogen oxygen species (RNOS), components of the inflammatory response, contribute to deleterious effects of inflammation. RNOS catalyze nitrosation, oxidation, and nitration reactions. However, the influence of RNOS on HCA carcinogenicity has not been evaluated. Such an evaluation is essential to understanding the strong association between cooked red meat intake and chronic infection/inflammation in colon cancer. Because we recently demonstrated RNOS transformation of IQ to an N-nitroso product N-NO-IQ), which forms DNA adducts and is mutagenic, we hypothesize that RNOS derived from the inflammatory response react with HCAs forming N-nitroso products that initiate colon cancer. Critical to testing this hypothesis is the identification and measurement of N-nitroso products in animals and cells responding to inflammatory stimuli; the demonstration that N-nitroso products are genotoxic and that HCA-induced colon cancer is increased in DSS-treated mice. The following specific aims will test our hypothesis: 1. Investigate HCA transformation by RNOS; 2. Determine reactivity and potential genotoxicity of HCAs and their RNOS-derived N-nitroso products; 3. Evaluate formation and metabolism of N-NO-IQ and its products by in vitro cellular systems, using inflammatory models; 4. Assess formation and metabolism of N-NO-IQ in mice with DSS-induced colitis; 5. Determine effect of DSS-induced colitis inflammation) in IQ carcinogenicity. The long-term goal is to understand the role of RNOS on HCA carcinogenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA072613-07
Application #
7115019
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Yang, Shen K
Project Start
1998-07-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
7
Fiscal Year
2006
Total Cost
$249,488
Indirect Cost
Name
Saint Louis University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
050220722
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
Hsu, Fong-Fu; Lakshmi, Vijaya M; Zenser, Terry V (2009) Characterization of new metabolites from in vivo biotransformation of 2-amino-3-methylimidazo[4,5-f]quinoline in mouse by mass spectrometry. J Mass Spectrom 44:1359-68
Lakshmi, Vijaya M; Hsu, Fong-Fu; Zenser, Terry V (2009) Identification of new 2-amino-3-methylimidazo[4,5-f]quinoline urinary metabolites from beta-naphthoflavone-treated mice. Drug Metab Dispos 37:1690-7
Zenser, Terry V; Lakshmi, Vijaya M; Schut, Herman A J et al. (2009) Activation of aminoimidazole carcinogens by nitrosation: mutagenicity and nucleotide adducts. Mutat Res 673:109-15
Lakshmi, Vijaya M; Hsu, Fong Fu; Zenser, Terry V (2008) N-Demethylation is a major route of 2-amino-3-methylimidazo[4,5-f]quinoline metabolism in mouse. Drug Metab Dispos 36:1143-52
Armbrecht, Harvey J; Lakshmi, Vijaya M; Wickstra, Jason et al. (2007) Metabolism of a heterocyclic amine colon carcinogen in young and old rats. Drug Metab Dispos 35:633-9
Lakshmi, Vijaya M; Zenser, Terry V (2007) 2-(4-Carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide potentiates nitrosation of a heterocyclic amine carcinogen by nitric oxide. Life Sci 80:644-9
Lakshmi, Vijaya M; Hsu, Fong Fu; Schut, Herman A J et al. (2006) Stability and reactivity of 2-nitrosoamino-3,8-dimethylimidazo[4,5-f]quinoxaline. Chem Res Toxicol 19:325-33
Lakshmi, Vijaya M; Nauseef, William M; Zenser, Terry V (2005) Myeloperoxidase potentiates nitric oxide-mediated nitrosation. J Biol Chem 280:1746-53
Lakshmi, Vijaya M; Schut, Herman A J; Zenser, Terry V (2005) 2-Nitrosoamino-3-methylimidazo[4,5-f]quinoline activated by the inflammatory response forms nucleotide adducts. Food Chem Toxicol 43:1607-17
Lakshmi, Vijaya M; Clapper, Margie L; Chang, Wen-Chi et al. (2005) Hemin potentiates nitric oxide-mediated nitrosation of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) to 2-nitrosoamino-3-methylimidazo[4,5-f]quinoline. Chem Res Toxicol 18:528-35

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