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 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) 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 noncarriers (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). For NNAL-N-glucuronide to be more precisely quantified 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, the 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.
Bibliographical noteFunding Information:
This study was supported by NCI grant P01 CA-138338. The LC/MS/MS analysis was carried out in the Analytical Biochemistry Core of the University of Minnesota Cancer Center supported in part by NCI P30 CA-077598. Genotyping for Study 2 was performed at the University of Hawaii Cancer Center Genomics Shared Resource supported by NCI CCSG grant P30 CA-071789.
*Phone: (612) 624-7633. Fax: (612) 624-3869. E-mail: firstname.lastname@example.org. ORCID Sharon E. Murphy: 0000-0001-5391-8104 Irina Stepanov: 0000-0001-5140-8944 Funding This study was supported by NCI grant P01 CA-138338. The LC/MS/MS analysis was carried out in the Analytical Biochemistry Core of the University of Minnesota Cancer Center supported in part by NCI P30 CA-077598. Genotyping for Study 2 was performed at the University of Hawaii Cancer Center Genomics Shared Resource supported by NCI CCSG grant P30 CA-071789. Notes The authors declare no competing financial interest.
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