The UDP-glucuronosyltransferase 2B17 gene deletion polymorphism: Sex-specific association with urinary 4-(methyinitrosamino)-1-(3-pyridyl)-1-butanol glucuroniclation phenotype and risk for lung cancer
The UDP-glucuronosyltransferase 2B17 gene deletion polymorphism: Sex-specific association with urinary 4-(methyinitrosamino)-1-(3-pyridyl)-1-butanol glucuroniclation phenotype and risk for lung cancer
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DOI：
10.1158/1055-9965.epi-06-0823
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发表时间：
2007-04-01
影响因子：
3.8
通讯作者：
Lazarus, Philip
中科院分区：
文献类型：
--
作者：
Gallagher, Carla J.;Muscat, Joshua E.;Lazarus, Philip
4-（甲基硝基氨基氨基）-1-（3-吡啶基）-1-丁酮是在烟草烟雾中发现的有效且丰富的procarcinegen，其主要代谢物的4--（甲基硝基氨基氨基）-1-1-1-（3-吡啶基）-1（3-吡啶基）-1-1-1-1-1-1-1（3-吡啶基）-1 - 丁醇（nnal），通过UDP-葡萄糖糖基转移酶（UGT），包括UGT2B17是4-（甲基硝基氨基）-1-（3-吡啶基）-1-丁酮排毒的重要机制。 UGT2B17基因的两个副本均与10％的白人相似，并且缺失与体外Nnal葡萄糖醛酸化活性的降低有关。在这项研究中，我们检查了82个健康的吸烟者样本中UGT2B17缺失（0/0）对NNAL葡萄糖醛酸化率的影响，并进一步研究了一项单独的病例对照研究中其对肺癌风险的影响。在健康吸烟者的研究中，与具有野生型或杂合基因型的女性相比，在UGT2B17缺失（0/0）的女性中观察到NNAL-葡萄糖醛酸与NNAN的尿比（0/0）（p = 0.058）。在男性中，基因型的比率没有显着差异（p = 0.597）。在398例肺癌患者和697个社区对照的病例对照研究中，UGT2B17缺失（0/0）与女性肺癌的风险显着增加有关（优势比2.0； 95％置信区间，1.01-1.01--1.01-- 4.0）。肺腺癌女性子集的风险为2.8（95％置信区间，1.2-6.3）。缺失与女性的其他肺组织学类型无关，并且与男性中任何肺组织学类型的风险无关。 UGT2B17缺失与女性肺腺癌增加的关联与女性的NNal葡萄糖lucuticlation速率的降低相一致，并且研究表明NNAL是实验动物中肺腺癌的选择性诱导剂。
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 similar to 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 glucuroniclation rates in women and with studies showing that NNAL is a selective inducer of lung adenocarcinoma in experimental animals.