Besides numerous toxic, carcinogenic, co-carcinogenic and tumor- promoting chemicals, cigarette smoke is a source of nitric oxide, and of quinones which generate superoxide by redox cycling. Superoxide is a potential source of hydrogen peroxide, a precursor of the highly destructive hydroxyl radical. Superoxide also combines spontaneously with nitric oxide to form peroxynitrite. The latter decomposes to a species with a reactivity similar to that of the hydroxy radical as well as to a species which is chemically similar to the nitronium ion, capable of nitrating aromatic amino acids in proteins. Numerous studies have shown that the reactive oxidizing and nitrating species that can be derived from cigarette smoke produce damage to lipids, proteins and DNA in vitro, and it is suspected that similar damage can occur in vivo. Further damage to the pulmonary system can take place when macrophages and neutrophils, attracted to the site of primary cellular damage caused by cigarette smoke, release proteolytic enzymes, HOCl, as well as additional amounts of nitric oxide and superoxide. Cells of the pulmonary system possess various defenses against oxidative damage, including the powerful antioxidants, ascorbic acid and alpha- tocopherol. It is well established that ascorbic acid is partially depleted in cigarette smokers, presumably through participation in antioxidant reactions. Surprisingly, neither the potential of cigarette smoke to cause specific oxidative damage, nor the possible protective effects of antioxidant vitamins have thus far been adequately studied in vivo. The goals of this program are to characterize oxidative and other damage produced in the pulmonary system of guinea pigs by exposure to cigarette smoke, and to determine the effects of dietary vitamins C and E on the process. The guinea pig was chosen as the experimental model because, of all rodent species, it most resembles man in requiring a dietary source of vitamin C.
Our specific aims are:, 1) To determine oxidative damage to DNA, RNA, proteins and lipids of the guinea pig lung and trachea produced by chronic exposure to cigarette smoke; 2) To systematically vary the dietary levels of vitamins C and E of cigarette smoke-exposed guinea pigs in order to determine possible protective (or enhancing) effects on pulmonary oxidative damage; 3) To attempt to separately estimate part of the initial damage caused by peroxynitrite derived from cigarette smoke by spiking the cigarettes used in these studies with 15N-labeled nitrate, and by quantitating 15N/14N ratios in 3-nitrotyrosine residues of respiratory tract proteins. The results obtained from our studies will be the first to comprehensively characterize oxidative damage due to cigarette smoke in an appropriate animal model, and will yield important information on the mechanisms involved. The studies will also furnish additional strong rationale for dietary antioxidant vitamin recommendations to those smokers who are unable to quit.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
1P01CA070972-03
Application #
6269764
Study Section
Project Start
1998-02-01
Project End
1999-01-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Institute for Cancer Prevention
Department
Type
DUNS #
City
Valhalla
State
NY
Country
United States
Zip Code
10595
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Chang, Sung Il; El-Bayoumy, Karam; Sinha, Indu et al. (2007) 4-(Methylnitrosamino)-I-(3-pyridyl)-1-butanone enhances the expression of apolipoprotein A-I and Clara cell 17-kDa protein in the lung proteomes of rats fed a corn oil diet but not a fish oil diet. Cancer Epidemiol Biomarkers Prev 16:228-35
Chen, Kun-Ming; Spratt, Thomas E; Stanley, Bruce A et al. (2007) Inhibition of nuclear factor-kappaB DNA binding by organoselenocyanates through covalent modification of the p50 subunit. Cancer Res 67:10475-83
Melikian, Assieh A; Djordjevic, Mirjana V; Hosey, James et al. (2007) Gender differences relative to smoking behavior and emissions of toxins from mainstream cigarette smoke. Nicotine Tob Res 9:377-87

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