Low Cotinine Glucuronidation Results in Higher Serum and Saliva Cotinine in African American Compared to White Smokers

Murphy, Sharon E.; Sipe, Christopher J.; Choi, Kwang-Soo; Raddatz, Leah M.; Koopmeiners, Joseph S.; Donny, Eric C.; Hatsukami, Dorothy K.

doi:10.1158/1055-9965.epi-16-0920

Cited by 21 publications

(41 citation statements)

References 24 publications

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“…21 We hypothesize that analogously African American smokers may have decreased NNAL N -glucuronidation and potentially decreased detoxication of the tobacco specific lung carcinogen NNK. In the study presented here we report on the influence of UGT2B10 genotype on NNAL glucuronidation in African American compared to white smokers.…”

Section: Introductionmentioning

confidence: 97%

Influence of UGT2B10 Genotype on Urinary Excretion of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol-N-glucuronide by African American Smokers

Murphy

Weymarn

Parenteau

et al. 2018

Chem. Res. Toxicol.

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At similar smoking levels African American’s lung cancer risk is as much as twice that of whites. We hypothesized that racial/ethnic differences in UDP-glucuronosyltransferase (UGT)-catalyzed glucuronidation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a detoxication pathway for the tobacco-specific lung carcinogen NNK (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone), may contribute to this variable risk. UGT2B10 catalyzes NNAL N-glucuronidation and a UGT2B10 splice variant is common among African Americans. Smokers from two independent studies were genotyped for this variant (rs116294140) and an Asp67Tyr variant (rs61750900), and urinary NNAL and NNAL glucuronide concentrations were quantified. In the first, no significant differences in NNAL-N-glucuronidation between African Americans (n=257) and whites (n=354), or between homozygous carriers of UGT2B10 variants (genetic score 2) and non-carriers (score 0) were detected. However, total NNAL glucuronidation by score 2 compared to score 0 smokers was lower (68.9% vs 71.2%, p<0.0001). To more precisely quantify NNAL N-glucuronide in a second study, a sensitive high resolution LC-MS/MS-based method, which separated NNAL, NNAL-O-glucuronide and NNAL-N-glucuronide prior to analysis, was developed. In this study, the excretion of total NNAL (free plus glucuronides) by African American (n=52) and white (n=54) smokers was not different, however, total NNAL glucuronidation by African Americans (64.0%) was slightly less than by whites (68.3%, p=0.05). The mean NNAL N-glucuronidation by African Americans was much lower than for whites (14% vs 24.9%, p<0.00001) but the NNAL O-glucuronidation was greater (50.0% vs 43.3%, p=0.013). UGT2B10 genotype influenced NNAL N-glucuronidation; the geometric mean percentage N-glucuronidation was 22.5% for smokers with genetic score 0 (n=57) and 11.2% for score 2 (n=11). In summary, the high prevalence of a UGT2B10 splice variant among African Americans results in lower NNAL N-glucuronidation but only a small decrease in total NNAL glucuronidation. Therefore despite the significant contribution of UGT2B10 to NNAL-N-glucuronidation, UGT2B10 genotype does not play a large role in NNAL detoxication. Any decrease in N-glucuronidation was accompanied by a parallel increase in O-glucuronidation.

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Section: Introductionmentioning

confidence: 97%

Influence of UGT2B10 Genotype on Urinary Excretion of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol-N-glucuronide by African American Smokers

Murphy

Weymarn

Parenteau

et al. 2018

Chem. Res. Toxicol.

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“…These results are consistent with previous studies where the levels of cotinine glucuronide are lower and the free cotinine higher in the urine of AA compared to white smokers. 15 The other metabolites did not show any significant difference in the levels between the two groups.…”

Section: Resultsmentioning

confidence: 79%

“…These results are consistent with our targeted analysis and previous studies and support the need to normalize the levels of nicotine metabolites to TNE, rather than to CPD, to account for the differences in the exposure levels or nicotine dose in smokers. 15 , 22 We have used the indirect measurement of glucuronide metabolites of nicotine such as cotinine glucuronide and trans -3-hydoxycotinine glucuronide (β-glucuronidase treatment), as reported previously by others, to allow appropriate comparison of our current results with previous studies that used such indirect approaches. 15 , 57 The targeted analysis of nicotine metabolites in the two groups confirmed the results of our metabolomics analysis and therefore provided more confidence in the identification of the other differentially regulated pathways even those not directly related to nicotine.…”

Section: Discussionmentioning

confidence: 99%

“… 19 , 61 The majority (mean = 78% in two studies) of the UGT2B10-null individuals were AA in a multi-ethnic study based on the racial/ethnic-specific frequency of the UGT2B10 splice variant. 15 Genetic variations in UGT enzyme activities are associated with increased risk of developing solid cancers including colon, GI, lung, liver, oral, orolaryngeal, and prostate, which indicates that these variants are likely involved in detoxification of various carcinogens. 62 Furthermore, the UGT2B10 splice variants common in AA have been shown to greatly increase drug exposure in this population and therefore should be considered in the treatment regimen.…”

Section: Discussionmentioning

confidence: 99%

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Metabolomics Profiles of Smokers from Two Ethnic Groups with Differing Lung Cancer Risk

Dator

Villalta

Thomson

et al. 2020

Chem. Res. Toxicol.

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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 ( ) 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.

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“…The direct method provided slightly higher estimations for TNE 6 and TNE 9 (Bland-Altman ratios of 1.23 and 1.22, respectively), but the correlation and regression coefficients for comparisons between the two methods remained high. TNE is the gold standard for estimating smoking dose and is superior to self-reported cigarettes per day which may be subject to variation in smoking intensity and/or self-report bias (47), and plasma COT which is affected by individual genetic variability in its formation and metabolism (48, 49). Accurate estimates of smoking dose is important for risk prediction models aimed at identifying individuals at higher risk for smoking-related diseases such as lung cancer (8), and for comparisons across ethnicities or sexes, both of which can influence the utility of COT (48).…”

Section: Discussionmentioning

confidence: 99%

A Comparison of Direct and Indirect Analytical Approaches to Measuring Total Nicotine Equivalents in Urine

Taghavi

Novalen

Lerman

et al. 2018

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Total nicotine equivalents (TNE), the sum of nicotine and metabolites in urine, is a valuable tool for evaluating nicotine exposure. Most methods for measuring TNE involve two-step enzymatic hydrolysis for indirect quantification of glucuronide metabolites. Here, we describe a rapid, low-cost direct LC/MS assay. In 139 smokers' urine samples, Bland-Altman, correlation, and regression analyses were used to investigate differences in quantification of nicotine and metabolites, TNE, and nicotine metabolite ratio (NMR) between direct and indirect LC/MS methods. DNA from a subset ( = 97 smokers) was genotyped for and, and the known impact of these variants was evaluated using urinary ratios determined by the direct versus indirect method. The direct method showed high accuracy (0%-9% bias) and precision (3%-14% coefficient of variation) with similar distribution of nicotine metabolites to literary estimates and good agreement between the direct and indirect methods for nicotine, cotinine, and 3-hydroxycotinine (ratios 0.99-1.07), but less agreement for their respective glucuronides (ratios 1.16-4.17). The direct method identified urinary 3HC+3HC-GLUC/COT as having the highest concordance with plasma NMR and provided substantially better estimations of the established genetic impact of glucuronidation variants compared with the indirect method. Direct quantification of nicotine and metabolites is less time-consuming and less costly, and provides accurate estimates of nicotine intake, metabolism rate, and the impact of genetic variation in smokers. Lower cost and maintenance combined with high accuracy and reproducibility make the direct method ideal for smoking biomarker, NMR, and pharmacogenomics studies. .

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Low Cotinine Glucuronidation Results in Higher Serum and Saliva Cotinine in African American Compared to White Smokers

Cited by 21 publications

References 24 publications

Influence of UGT2B10 Genotype on Urinary Excretion of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol-N-glucuronide by African American Smokers

Influence of UGT2B10 Genotype on Urinary Excretion of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol-N-glucuronide by African American Smokers

Metabolomics Profiles of Smokers from Two Ethnic Groups with Differing Lung Cancer Risk

A Comparison of Direct and Indirect Analytical Approaches to Measuring Total Nicotine Equivalents in Urine

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