Dataset Information

Variation in levels of the lung carcinogen NNAL and its glucuronides in the urine of cigarette smokers from five ethnic groups with differing risks for lung cancer.

ABSTRACT: Results of the Multiethnic Cohort (MEC) study demonstrated that, for the same quantity of cigarettes smoked, African Americans and Native Hawaiians have a higher risk of lung cancer compared with whites, whereas Latinos and Japanese Americans have a lower risk. We hypothesize that the uptake and/or metabolism of the lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) could explain the differences in lung cancer risk.We measured urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides and their sum (total NNAL), biomarkers of NNK uptake, in 2,252 smokers from the MEC. Ethnic-specific geometric means were compared adjusting for age at urine collection, sex, creatinine and total nicotine equivalents, a marker of total nicotine uptake.African Americans had the highest median total NNAL levels (1.80 pmol/mL urine) and Japanese Americans had the lowest (0.914 pmol/mL urine), with intermediate values in the other three groups. Geometric mean of total NNAL in African Americans was also highest, and in Japanese Americans it was lowest; Japanese American geometric mean was statistically different from whites (P = 0.004).African Americans had higher levels of total NNAL per mL urine than whites, while Japanese Americans had lower levels, consistent with lung cancer risk among smokers in these groups. However, our data were not consistent with the high and low lung cancer risks of Native Hawaiian and Latino smokers, respectively.The higher lung cancer susceptibility of African-American smokers and the lower susceptibility of Japanese-American smokers compared with whites can be explained in part by exposure to the potent lung carcinogen NNK. Cancer Epidemiol Biomarkers Prev; 24(3); 561-9. ©2014 AACR.

SUBMITTER: Park SL

PROVIDER: S-EPMC4355389 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Variation in levels of the lung carcinogen NNAL and its glucuronides in the urine of cigarette smokers from five ethnic groups with differing risks for lung cancer.

Park Sungshim L SL Carmella Steven G SG Ming Xun X Vielguth Elizabeth E Stram Daniel O DO Le Marchand Loic L Hecht Stephen S SS

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20141226 3

<h4>Background</h4>Results of the Multiethnic Cohort (MEC) study demonstrated that, for the same quantity of cigarettes smoked, African Americans and Native Hawaiians have a higher risk of lung cancer compared with whites, whereas Latinos and Japanese Americans have a lower risk. We hypothesize that the uptake and/or metabolism of the lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) could explain the differences in lung cancer risk.<h4>Methods</h4>We measured urinary 4-(methy ...[more]

PMID: 25542827

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Project description:Results from the Multiethnic Cohort Study demonstrated significant differences in lung cancer risk among cigarette smokers from five different ethnic/racial groups. For the same number of cigarettes smoked, and particularly among light smokers, African Americans and Native Hawaiians had the highest risk for lung cancer, Whites had intermediate risk, while Latinos and Japanese Americans had the lowest risk. We analyzed urine samples from 331-709 participants from each ethnic group in this study for metabolites of phenanthrene, a surrogate for carcinogenic polycyclic aromatic hydrocarbon exposure. Consistent with their lung cancer risk and our previous studies of several other carcinogens and toxicants of cigarette smoke, African Americans had significantly (p<0.0001) higher median levels of the two phenanthrene metabolites 3-hydroxyphenanthrene (3-PheOH, 0.931 pmol/ml) and phenanthrene tetraol (PheT, 1.13 pmol/ml) than Whites (3-PheOH, 0.697 pmol/ml; PheT, 0.853 pmol/ml) while Japanese-Americans had significantly (p = 0.002) lower levels of 3-PheOH (0.621 pmol/ml) than Whites. PheT levels (0.838 pmol/ml) in Japanese-Americans were not different from those of Whites. These results are mainly consistent with the lung cancer risk of these three groups, but the results for Native Hawaiians and Latinos were more complex. We also carried out a genome wide association study in search of factors that could influence PheT and 3-PheOH levels. Deletion of GSTT1 explained 2.2% of the variability in PheT, while the strongest association, rs5751777 (p = 1.8x10-62) in the GSTT2 gene, explained 7.7% of the variability in PheT. These GWAS results suggested a possible protective effect of lower GSTT1 copy number variants on the diol epoxide pathway, which was an unexpected result. Collectively, the results of this study provide further evidence that different patterns of cigarette smoking are responsible for the higher lung cancer risk of African Americans than of Whites and the lower lung cancer risk of Japanese Americans, while other factors appear to be involved in the differing risks of Native Hawaiians and Latinos.

Project description:African American (AA) smokers are at a higher risk of developing lung cancer compared to whites. The variations in the metabolism of nicotine and tobacco-derived carcinogens in these groups were reported previously with the levels of nicotine metabolites and carcinogen-derived metabolites measured using targeted approaches. While useful, these targeted strategies are not able to detect global metabolic changes for use in predicting the detrimental effects of tobacco use and ultimately lung cancer susceptibility among smokers. To address this limitation, we have performed global untargeted metabolomics profiling in urine of AA and white smokers to characterize the pattern of metabolites, identify differentially regulated pathways, and correlate these profiles with the observed variations in lung cancer risk between these two populations. Urine samples from AA (n = 30) and white (n = 30) smokers were used for metabolomics analysis acquired in both positive and negative electrospray ionization modes. LC-MS data were uploaded onto the cloud-based XCMS online (http://xcmsonline.scripps.edu) platform for retention time correction, alignment, feature detection, annotation, statistical analysis, data visualization, and automated systems biology pathway analysis. The latter identified global differences in the metabolic pathways in the two groups including the metabolism of carbohydrates, amino acids, nucleotides, fatty acids, and nicotine. Significant differences in the nicotine degradation pathway (cotinine glucuronidation) in the two groups were observed and confirmed using a targeted LC-MS/MS approach. These results are consistent with previous studies demonstrating AA smokers with lower glucuronidation capacity compared to whites. Furthermore, the d-glucuronate degradation pathway was found to be significantly different between the two populations, with lower amounts of the putative metabolites detected in AA compared to whites. We hypothesize that the differential regulation of the d-glucuronate degradation pathway is a consequence of the variations in the glucuronidation capacity observed in the two groups. Other pathways including the metabolism of amino acids, nucleic acids, and fatty acids were also identified, however, the biological relevance and implications of these differences across ethnic groups need further investigation. Overall, the applied metabolomics approach revealed global differences in the metabolic networks and endogenous metabolites in AA and whites, which could be used and validated as a new potential panel of biomarkers that could be used to predict lung cancer susceptibility among smokers in population-based studies.

Dataset Information

Variation in levels of the lung carcinogen NNAL and its glucuronides in the urine of cigarette smokers from five ethnic groups with differing risks for lung cancer.

Publications

Variation in levels of the lung carcinogen NNAL and its glucuronides in the urine of cigarette smokers from five ethnic groups with differing risks for lung cancer.

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