Dataset Information

The Impact of One-week Dietary Supplementation with Kava on Biomarkers of Tobacco Use and Nitrosamine-based Carcinogenesis Risk among Active Smokers.

ABSTRACT: Tobacco smoking is the primary risk factor for lung cancer, driven by the addictive nature of nicotine and the indisputable carcinogenicity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) as well as other compounds. The integration of lung cancer chemoprevention with smoking cessation is one potential approach to reduce this risk and mitigate lung cancer mortality. Experimental data from our group suggest that kava, commonly consumed in the South Pacific Islands as a beverage to promote relaxation, may reduce lung cancer risk by enhancing NNK detoxification and reducing NNK-derived DNA damage. Building upon these observations, we conducted a pilot clinical trial to evaluate the effects of a 7-day course of kava on NNK metabolism in active smokers. The primary objective was to compare urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL plus its glucuronides, major metabolites of NNK) before and after kava administration as an indicator of NNK detoxification. Secondary objectives included determining kava's safety, its effects on DNA damage, tobacco use, and cortisol (a biomarker of stress). Kava increased urinary excretion of total NNAL and reduced urinary 3-methyladenine in participants, suggestive of its ability to reduce the carcinogenicity of NNK. Kava also reduced urinary total nicotine equivalents, indicative of its potential to facilitate tobacco cessation. Plasma cortisol and urinary total cortisol equivalents were reduced upon kava use, which may contribute to reductions in tobacco use. These results demonstrate the potential of kava intake to reduce lung cancer risk among smokers.

SUBMITTER: Wang Y

PROVIDER: S-EPMC7461349 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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The Impact of One-week Dietary Supplementation with Kava on Biomarkers of Tobacco Use and Nitrosamine-based Carcinogenesis Risk among Active Smokers.

Wang Yi Y Narayanapillai Sreekanth C SC Tessier Katelyn M KM Strayer Lori G LG Upadhyaya Pramod P Hu Qi Q Kingston Rick R Salloum Ramzi G RG Lu Junxuan J Hecht Stephen S SS Hatsukami Dorothy K DK Fujioka Naomi N Xing Chengguo C

Cancer prevention research (Philadelphia, Pa.) 20200226 5

Tobacco smoking is the primary risk factor for lung cancer, driven by the addictive nature of nicotine and the indisputable carcinogenicity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) as well as other compounds. The integration of lung cancer chemoprevention with smoking cessation is one potential approach to reduce this risk and mitigate lung cancer mortality. Experimental data from our group suggest that kava, commonly consumed in the South Pacific Islands as a beverage to promote ...[more]

PMID: 32102948

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Project description:N'-nitrosonornicotine (NNN) is one of the tobacco-specific nitrosamines (TSNAs) that exists widely in smoke and smokeless tobacco products. NNN can induce tumors in various laboratory animal models and has been identified by International Agency for Research on Cancer (IARC) as a human carcinogen. Metabolic activation of NNN is primarily initiated by cytochrome P450 enzymes (CYP450s) via 2'-hydroxylation or 5'-hydroxylation. Subsequently, the hydroxylating intermediates undergo spontaneous decomposition to generate diazohydroxides, which can be further converted to alkyldiazonium ions, followed by attacking DNA to form various DNA damages, such as pyridyloxobutyl (POB)-DNA adducts and pyridyl-N-pyrrolidinyl (py-py)-DNA adducts. If not repaired correctly, these lesions would lead to tumor formation. In the present study, we performed density functional theory (DFT) computations and molecular docking studies to understand the mechanism of metabolic activation and carcinogenesis of NNN. DFT calculations were performed to explore the 2'- or 5'- hydroxylation reaction of (R)-NNN and (S)-NNN. The results indicated that NNN catalyzed by the ferric porphyrin (Compound I, Cpd I) at the active center of CYP450 included two steps, hydrogen abstraction and rebound reactions. The free energy barriers of the 2'- and 5'-hydroxylation of NNN are 9.82/8.44 kcal/mol (R/S) and 7.99/9.19 kcal/mol (R/S), respectively, suggesting that the 2'-(S) and 5'-(R) pathways have a slight advantage. The free energy barriers of the decomposition occurred at the 2'-position and 5'-position of NNN are 18.04/18.02 kcal/mol (R/S) and 18.33/19.53 kcal/mol (R/S), respectively. Moreover, we calculated the alkylation reactions occurred at ten DNA base sites induced by the 2'-hydroxylation product of NNN, generating the free energy barriers ranging from 0.86 to 4.72 kcal/mol, which indicated that these reactions occurred easily. The docking study showed that (S)-NNN had better affinity with CYP450s than that of (R)-NNN, which was consistent with the experimental results. Overall, the combined results of the DFT calculations and the docking obtained in this study provide an insight into the understanding of the carcinogenesis of NNN and other TSNAs.

Project description:Smokeless tobacco products, such as moist snuff or chewing tobacco, contain many of the same carcinogens as tobacco smoke; however, the impact on children of indirect exposure to tobacco constituents via parental smokeless tobacco use is unknown. As part of the California Childhood Leukemia Study, dust samples were collected from 6 homes occupied by smokeless tobacco users, 6 homes occupied by active smokers, and 20 tobacco-free homes. To assess children's potential for exposure to tobacco constituents, vacuum-dust concentrations of five tobacco-specific nitrosamines, including N'-nitrosonornicotine [NNN] and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone [NNK], as well as six tobacco alkaloids, including nicotine and myosmine, were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). We used generalized estimating equations derived from a multivariable marginal model to compare levels of tobacco constituents between groups, after adjusting for a history of parental smoking, income, home construction date, and mother's age and race/ethnicity. The ratio of myosmine/nicotine was used as a novel indicator of the source of tobacco contamination, distinguishing between smokeless tobacco products and tobacco smoke. Median dust concentrations of NNN and NNK were significantly greater in homes with smokeless tobacco users compared to tobacco-free homes. In multivariable models, concentrations of NNN and NNK were 4.8- and 6.9-fold higher, respectively, in homes with smokeless tobacco users compared to tobacco-free homes. Median myosmine/nicotine ratios were lower in homes with smokeless tobacco users (1.8%) compared to homes of active smokers (7.7%), confirming that cigarette smoke was not the predominant source of tobacco constituents in homes with smokeless tobacco users. Children living with smokeless tobacco users may be exposed to carcinogenic tobacco-specific nitrosamines via contact with contaminated dust and household surfaces.

Dataset Information

The Impact of One-week Dietary Supplementation with Kava on Biomarkers of Tobacco Use and Nitrosamine-based Carcinogenesis Risk among Active Smokers.

Publications

The Impact of One-week Dietary Supplementation with Kava on Biomarkers of Tobacco Use and Nitrosamine-based Carcinogenesis Risk among Active Smokers.

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