The proposed research as a high probability of identifying important chemical features which both predispose and serve to block or inhibit the rapid formation of carcinogenic nitrosamines from certain nitrogen compounds both in vivo and in the environment. There are many gaps in our knowledge of the molecular and other chemical factors which lead to rapid or significant nitrosamine formation. It is not know, for example, how nitrosamines are formed in cosmetics, shampoos, other toiletry items, metalworking fluids, and tobacco. Endogenous formation of many N-nitroso compounds may go undetected because of their rapid and possible injurious metabolism. We believe that a fundamental understanding of the chemistry of the nitrosation process, particularly as it relates to ternary nitrogen compounds, can lead to methods for eliminating or decreasing exposure to nitrosamines and thereby prevent human cancer. The rapid formation of nitrosamines from ternary nitrogen compounds including tertiary amines containing an electron rich aromatic ring, tertiary amidines, and gem diamines, will be examined with respect to the necessary structural features and the variables of endogenous nitrosation, nitrite level, pH, and - SCN concentration. Several complex drugs and food constituents including reserpine, hexetidine, methaphenaline, amidinocillin and medibazine will be screened for mutagenicity. Pyrroles and polymers containing pyrroles will be examined for their ability to block nitrosamine formation. Ester mediated nitrosation, a reaction discovered through this research and possibly responsible for inadvertent nitrosamine formation in commercial samples, will be further elucidated.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA026914-11
Application #
3482076
Study Section
Pathology B Study Section (PTHB)
Project Start
1980-02-01
Project End
1991-11-30
Budget Start
1990-12-01
Budget End
1991-11-30
Support Year
11
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Missouri-Columbia
Department
Type
Schools of Arts and Sciences
DUNS #
112205955
City
Columbia
State
MO
Country
United States
Zip Code
65211
Loeppky, Richard N; Shi, Jianzheng; Barnes, Charles L et al. (2008) A diazonium ion cascade from the nitrosation of tolazoline, an imidazoline-containing drug. Chem Res Toxicol 21:295-307
Teuten, Emma L; Loeppky, Richard N (2005) The mechanistic origin of regiochemical changes in the nitrosative N-dealkylation of N,N-dialkyl aromatic amines. Org Biomol Chem 3:1097-108
Loeppky, Richard N; Yu, Hongbin (2004) Amidine nitrosation. J Org Chem 69:3015-24
Loeppky, R N; Elomari, S (2000) N-Alkyl-N-cyclopropylanilines as mechanistic probes in the nitrosation of N,N-dialkyl aromatic amines. J Org Chem 65:96-103
Bae, J Y; Mende, P; Shevlin, G et al. (1994) The nitrosation of hexetidine and hexedine: characterization of the major nitrosamine from common antimicrobial agents. Chem Res Toxicol 7:868-76
Loeppky, R N; Bae, J Y (1994) An aziridinium ion intermediate in the nitrosation of a hexetidine model. Chem Res Toxicol 7:861-7
Wilcox, A L; Bao, Y T; Loeppky, R N (1991) Pyrroles as effective agents for blocking amine nitrosation. Chem Res Toxicol 4:373-81
Bao, Y T; Loeppky, R N (1991) Blocking nitrosamine formation with polymers. Chem Res Toxicol 4:382-9
Loeppky, R N; Tomasik, W; Kerrick, B E (1987) Nitroso transfer from alpha-nitrosamino aldehydes: implications for carcinogenesis. Carcinogenesis 8:941-6