The UDP-glucuronosyltransferase 2B17 gene deletion polymorphism

Sex-specific association with urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanol glucuronidation phenotype and risk for lung cancer

Carla J. Gallagher, Joshua Muscat, Amy N. Hicks, Yan Zheng, Anne Marie Dyer, Gary A. Chase, John Richie, Philip Lazarus

Research output: Contribution to journalArticle

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Abstract

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone is a potent and abundant procarcinogen found in tobacco smoke, and glucuronidation of its major metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), by UDP-glucuronosyltransferases (UGT) including UGT2B17 is an important mechanism for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone detoxification. Both copies of the UGT2B17 gene are deleted in ∼10% of Whites and the deletion is associated with a reduction in NNAL glucuronidation activity in vitro. In this study, we examined the effects of the UGT2B17 deletion (0/0) on NNAL glucuronidation rates in a sample of 82 healthy cigarette smokers and further examined its effects on lung cancer risk in a separate case-control study. In the healthy smokers study, a lower urinary ratio of NNAL-glucuronide to NNAL was observed in women with the UGT2B17 deletion (0/0) as compared with women with either the wild-type or heterozygous genotypes (P = 0.058). There were no significant differences in this ratio by genotype in men (P = 0.597). In the case-control study of 398 lung cancer patients and 697 community controls, the UGT2B17 deletion (0/0) was associated with a significant increase in risk of lung cancer in women (odds ratio, 2.0; 95% confidence interval, 1.01-4.0). The risk for the subset of women with lung adenocarcinoma was 2.8 (95% confidence interval, 1.2-6.3). The deletion was not associated with other lung histologic types in women and was not associated with the risk for any lung histologic types in men. The association of the UGT2B17 deletion with increased lung adenocarcinoma in women is consistent with its association with decreased NNAL glucuronidation rates in women and with studies showing that NNAL is a selective inducer of lung adenocarcinoma in experimental animals.

Original languageEnglish (US)
Pages (from-to)823-828
Number of pages6
JournalCancer Epidemiology Biomarkers and Prevention
Volume16
Issue number4
DOIs
StatePublished - Apr 1 2007

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Glucuronosyltransferase
Gene Deletion
Lung Neoplasms
Phenotype
Case-Control Studies
Genotype
Confidence Intervals
Lung
Glucuronides
4-(methylnitrosamino)-1-(3-pyridyl)-1-butan-1-ol
Smoke
Tobacco Products
Tobacco
Odds Ratio
Genes

All Science Journal Classification (ASJC) codes

  • Epidemiology
  • Oncology

Cite this

@article{32484ee57c1a4708ac448229edaf0eda,
title = "The UDP-glucuronosyltransferase 2B17 gene deletion polymorphism: Sex-specific association with urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanol glucuronidation phenotype and risk for lung cancer",
abstract = "4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone is a potent and abundant procarcinogen found in tobacco smoke, and glucuronidation of its major metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), by UDP-glucuronosyltransferases (UGT) including UGT2B17 is an important mechanism for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone detoxification. Both copies of the UGT2B17 gene are deleted in ∼10{\%} of Whites and the deletion is associated with a reduction in NNAL glucuronidation activity in vitro. In this study, we examined the effects of the UGT2B17 deletion (0/0) on NNAL glucuronidation rates in a sample of 82 healthy cigarette smokers and further examined its effects on lung cancer risk in a separate case-control study. In the healthy smokers study, a lower urinary ratio of NNAL-glucuronide to NNAL was observed in women with the UGT2B17 deletion (0/0) as compared with women with either the wild-type or heterozygous genotypes (P = 0.058). There were no significant differences in this ratio by genotype in men (P = 0.597). In the case-control study of 398 lung cancer patients and 697 community controls, the UGT2B17 deletion (0/0) was associated with a significant increase in risk of lung cancer in women (odds ratio, 2.0; 95{\%} confidence interval, 1.01-4.0). The risk for the subset of women with lung adenocarcinoma was 2.8 (95{\%} confidence interval, 1.2-6.3). The deletion was not associated with other lung histologic types in women and was not associated with the risk for any lung histologic types in men. The association of the UGT2B17 deletion with increased lung adenocarcinoma in women is consistent with its association with decreased NNAL glucuronidation rates in women and with studies showing that NNAL is a selective inducer of lung adenocarcinoma in experimental animals.",
author = "Gallagher, {Carla J.} and Joshua Muscat and Hicks, {Amy N.} and Yan Zheng and Dyer, {Anne Marie} and Chase, {Gary A.} and John Richie and Philip Lazarus",
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The UDP-glucuronosyltransferase 2B17 gene deletion polymorphism : Sex-specific association with urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanol glucuronidation phenotype and risk for lung cancer. / Gallagher, Carla J.; Muscat, Joshua; Hicks, Amy N.; Zheng, Yan; Dyer, Anne Marie; Chase, Gary A.; Richie, John; Lazarus, Philip.

In: Cancer Epidemiology Biomarkers and Prevention, Vol. 16, No. 4, 01.04.2007, p. 823-828.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The UDP-glucuronosyltransferase 2B17 gene deletion polymorphism

T2 - Sex-specific association with urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanol glucuronidation phenotype and risk for lung cancer

AU - Gallagher, Carla J.

AU - Muscat, Joshua

AU - Hicks, Amy N.

AU - Zheng, Yan

AU - Dyer, Anne Marie

AU - Chase, Gary A.

AU - Richie, John

AU - Lazarus, Philip

PY - 2007/4/1

Y1 - 2007/4/1

N2 - 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone is a potent and abundant procarcinogen found in tobacco smoke, and glucuronidation of its major metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), by UDP-glucuronosyltransferases (UGT) including UGT2B17 is an important mechanism for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone detoxification. Both copies of the UGT2B17 gene are deleted in ∼10% of Whites and the deletion is associated with a reduction in NNAL glucuronidation activity in vitro. In this study, we examined the effects of the UGT2B17 deletion (0/0) on NNAL glucuronidation rates in a sample of 82 healthy cigarette smokers and further examined its effects on lung cancer risk in a separate case-control study. In the healthy smokers study, a lower urinary ratio of NNAL-glucuronide to NNAL was observed in women with the UGT2B17 deletion (0/0) as compared with women with either the wild-type or heterozygous genotypes (P = 0.058). There were no significant differences in this ratio by genotype in men (P = 0.597). In the case-control study of 398 lung cancer patients and 697 community controls, the UGT2B17 deletion (0/0) was associated with a significant increase in risk of lung cancer in women (odds ratio, 2.0; 95% confidence interval, 1.01-4.0). The risk for the subset of women with lung adenocarcinoma was 2.8 (95% confidence interval, 1.2-6.3). The deletion was not associated with other lung histologic types in women and was not associated with the risk for any lung histologic types in men. The association of the UGT2B17 deletion with increased lung adenocarcinoma in women is consistent with its association with decreased NNAL glucuronidation rates in women and with studies showing that NNAL is a selective inducer of lung adenocarcinoma in experimental animals.

AB - 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone is a potent and abundant procarcinogen found in tobacco smoke, and glucuronidation of its major metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), by UDP-glucuronosyltransferases (UGT) including UGT2B17 is an important mechanism for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone detoxification. Both copies of the UGT2B17 gene are deleted in ∼10% of Whites and the deletion is associated with a reduction in NNAL glucuronidation activity in vitro. In this study, we examined the effects of the UGT2B17 deletion (0/0) on NNAL glucuronidation rates in a sample of 82 healthy cigarette smokers and further examined its effects on lung cancer risk in a separate case-control study. In the healthy smokers study, a lower urinary ratio of NNAL-glucuronide to NNAL was observed in women with the UGT2B17 deletion (0/0) as compared with women with either the wild-type or heterozygous genotypes (P = 0.058). There were no significant differences in this ratio by genotype in men (P = 0.597). In the case-control study of 398 lung cancer patients and 697 community controls, the UGT2B17 deletion (0/0) was associated with a significant increase in risk of lung cancer in women (odds ratio, 2.0; 95% confidence interval, 1.01-4.0). The risk for the subset of women with lung adenocarcinoma was 2.8 (95% confidence interval, 1.2-6.3). The deletion was not associated with other lung histologic types in women and was not associated with the risk for any lung histologic types in men. The association of the UGT2B17 deletion with increased lung adenocarcinoma in women is consistent with its association with decreased NNAL glucuronidation rates in women and with studies showing that NNAL is a selective inducer of lung adenocarcinoma in experimental animals.

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