Abstract 4152: Differences in nicotine metabolism among five racial/ethnic groups with disparate risks for lung cancer: The multiethnic cohort study
Authors: Park Sung-Shim L. , Caberto Christian , Tiirikainen Maarit , Wilkens Lynne , Stram Daniel , Haiman Christopher A. , Hecht Stephen S. , Murphy Sharon , Marchand Loic L. 
Published: May 2015

Abstract
Introduction: Globally, lung cancer is the most common cancer and the leading cause of cancer-related deaths. Smoking is a well-established risk factor for this disease; however, self-reported dose does not fully explain the differences in lung cancer risk observed across ethnic/racial populations. Compared to whites, for the same lifetime number of cigarettes smoked, African Americans (AA) and Native Hawaiians (NH) have substantially higher rates of lung cancer, whereas Japanese Americans (JA) and Latinos (LA) have lower rates of disease. These differences may be due to variations in nicotine metabolism, thereby influencing smoking behavior.
Methods: Using overnight or first morning urine samples collected in the Multiethnic Cohort study (MEC), we examined nicotine metabolism among 2,300 cancer-free smokers of five racial/ethnic groups with different lung cancer risks: AA (n=356), NH (n=330), whites (n=444), LA (n=459) and JA (n=711). Total and free urinary nicotine metabolites: nicotine, cotinine, and trans-3-hydroxycotinine (3-OH) were measured by liquid chromatography tandem mass spectrometry. Smoking dose was quantified by urinary nicotine equivalents (NE)=total cotinine + total nicotine + total 3-OH. The respective glucuronidation ratio of each metabolite was calculated as the total metabolite minus the free metabolite divided by the free metabolite. CYP2A6 enzymatic activity ratio was calculated as: (total cotinine + 3-OH)/ NE. To examine the difference in metabolite levels across racial/ethnic groups, covariate-adjusted geometric means were computed for each group from linear regression models, adjusting for age at urine collection, sex, creatinine, BMI, and CYP2A6 activity ratio (for the NE and glucuronides models), cigarettes per day (CPD) (for the NE model) or NE (for the glucuronides and CYP2A6 activity models).
Results: We found that NE and nicotine, cotinine and 3-OH glucuronidation and CYP2A6 activity differed by race/ethnicity (p≤0.002). For NE, AA had the highest levels, followed by whites, LA, NH and JA (geometric means=30.9, 28.5, 28.3, 27.2 and 25.7 nmol/mL, respectively). For CYP2A6 activity, the ratio was highest in AA, followed by LA, whites, NH and JA (geometric means= 0.80, 0.81, 0.77, 0.73 and 0.62, respectively). We found that for each racial/ethnic group NE was greater for smokers in the higher compared to the lower tertile of CYP2A6 activity. This trend was significant for all groups, except NH (p-trend's= 0.02 [AA], 0.30 [NH], &lt;0.0001 [W, LA and JA]; p-interaction&lt;0.005).
Conclusion: CYP2A6 enzymatic activity affects smoking dose beyond CPD, which in part may explain the relatively lower risk of lung cancer of Japanese Americans. Further investigation of racial differences in lung cancer risk using nicotine biomarkers is warranted.
Citation Format: Sung-Shim L. Park, Christian Caberto, Maarit Tiirikainen, Lynne Wilkens, Daniel Stram, Christopher A. Haiman, Stephen S. Hecht, Sharon Murphy, Loic Le Marchand. Differences in nicotine metabolism among five racial/ethnic groups with disparate risks for lung cancer: The multiethnic cohort study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4152. doi:10.1158/1538-7445.AM2014-4152