Smoking-induced lung cancer is a major cause of cancer mortality in the US and worldwide. While 11–24% of smokers will develop lung cancer, risk varies among individuals and ethnic/racial groups. Specifically, African American and Native Hawaiian cigarette smokers are more likely to get lung cancer as compared to Caucasians, Japanese Americans, and Latinos. It is important to identify smokers who are at the greatest risk of developing lung cancer as they should be candidates for smoking cessation and chemopreventive intervention programs. Among 60+ tobacco smoke carcinogens, 1,3-butadiene (BD) is one of the most potent and abundant (20–75 μg per cigarette in mainstream smoke and 205–361 μg per cigarette in side stream smoke). BD is metabolically activated to 3,4-epoxy-1-butene (EB), which can be detoxified by glutathione S-transferase theta 1 (GSTT1)-mediated conjugation with glutathione, or can react with DNA to form 7-(1-hydroxy-3-buten-2-yl)guanine (EB-GII) adducts. In the present study, we employed EBV-transformed human lymphoblastoid cell lines (HapMap cells) with known GSTT1 genotypes to examine the influence of the GSTT1 gene on interindividual variability in butadiene metabolism, DNA adduct formation/repair, and biological outcomes (apoptosis). We found that GSTT1^– HapMap cells treated with EB in culture produced lower levels of glutathione conjugates and were more susceptible to apoptosis but had similar numbers of EB-GII adducts as GSTT1⁺ cells. Our results suggest that GSTT1 can influence an individual’s susceptibility to butadiene-derived epoxides.

中文翻译：

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人类HapMap细胞系中DNA加合物形成和1,3-丁二烯衍生的环氧化物解毒的个体差异。

在美国和世界范围内，吸烟引起的肺癌是导致癌症死亡的主要原因。尽管11–24％的吸烟者会患肺癌，但风险在个体和种族/种族之间有所不同。特别是，与高加索人，日裔美国人和拉丁美洲人相比，非洲裔美国人和夏威夷土著吸烟者更容易患肺癌。确定最容易患肺癌的吸烟者非常重要，因为他们应该是戒烟和化学预防干预计划的候选人。在60多种烟草烟雾致癌物中，1,3-丁二烯（BD）是最有效和含量最高的一种（主流烟雾中每支香烟20-75μg，侧流烟雾中每支香烟205-361μg）。BD被代谢激活为3,4-环氧-1-丁烯（EB），可以通过谷胱甘肽S-转移酶theta 1（GSTT1）介导的与谷胱甘肽的结合解毒，也可以与DNA反应形成7-（1-羟基-3-丁烯-2-基）鸟嘌呤（EB-GII）加合物。在本研究中，我们采用了已知的EBV转化人淋巴母细胞样细胞系（HapMap细胞）GSTT1基因型，以检查GSTT1基因对丁二烯代谢，DNA加合物形成/修复和生物学结果（凋亡）个体间变异性的影响。我们发现，在培养物中用EB处理的GSTT1 ^– HapMap细胞产生的谷胱甘肽结合物水平较低，对细胞凋亡更敏感，但其EB-GII加合物的数量与GSTT1 ⁺细胞相似。我们的结果表明，GSTT1可以影响个人对丁二烯衍生的环氧化物的敏感性。