ArticleChemical research in toxicology2018
Influence of UGT2B10 Genotype on Urinary Excretion of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol- N-glucuronide by African American Smokers.
Article in Chemical research in toxicology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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2 citing papers in PubMed, 6 citations in OpenAlex.
- Concentrations of Cotinine and 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol (NNAL) in U.S. Non-Daily Cigarette Smokers.Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology · 2021Article
- Role of l- and d-Menthol in the Glucuronidation and Detoxification of the Major Lung Carcinogen, NNAL.Drug metabolism and disposition: the biological fate of chemicals · 2019Article
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7 authors at 3 institutions in 1 country.
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Abstract
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.
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