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

Sharon E Murphy, Linda B von Weymarn, Marc Parenteau, Irina Stepanov, Maarit Tiirikainen, Loic Lemarchand, Sungshim L. Park

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)168-175
Number of pages8
JournalChemical Research in Toxicology
Volume31
Issue number3
DOIs
StatePublished - Mar 19 2018

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Glucuronides
African Americans
Genotype
Glucuronosyltransferase
Tobacco
Carcinogens
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol N-glucuronide
Lung Neoplasms
Smoking
Lung

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

Cite this

Influence of UGT2B10 Genotype on Urinary Excretion of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol- N- glucuronide by African American Smokers. / Murphy, Sharon E; von Weymarn, Linda B; Parenteau, Marc; Stepanov, Irina; Tiirikainen, Maarit; Lemarchand, Loic; Park, Sungshim L.

In: Chemical Research in Toxicology, Vol. 31, No. 3, 19.03.2018, p. 168-175.

Research output: Contribution to journalArticle

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title = "Influence of UGT2B10 Genotype on Urinary Excretion of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol- N- glucuronide by African American Smokers",
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.",
author = "Murphy, {Sharon E} and {von Weymarn}, {Linda B} and Marc Parenteau and Irina Stepanov and Maarit Tiirikainen and Loic Lemarchand and Park, {Sungshim L.}",
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T1 - Influence of UGT2B10 Genotype on Urinary Excretion of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol- N- glucuronide by African American Smokers

AU - Murphy, Sharon E

AU - von Weymarn, Linda B

AU - Parenteau, Marc

AU - Stepanov, Irina

AU - Tiirikainen, Maarit

AU - Lemarchand, Loic

AU - Park, Sungshim L.

PY - 2018/3/19

Y1 - 2018/3/19

N2 - 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.

AB - 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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