Comparison of polymorphisms in genes involved in polycyclic aromatic hydrocarbon metabolism with urinary phenanthrene metabolite ratios in smokers
Comparison of polymorphisms in genes involved in polycyclic aromatic hydrocarbon metabolism with urinary phenanthrene metabolite ratios in smokers
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DOI：
10.1158/1055-9965.epi-06-0173
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发表时间：
2006-10-01
影响因子：
3.8
通讯作者：
Hatsukami, Dorothy K.
中科院分区：
文献类型：
--
作者：
Hecht, Stephen S.;Carmella, Steven G.;Hatsukami, Dorothy K.
吸烟者多环芳烃（PAH）代谢的个体差异与肺癌风险相关的假设已在文献中得到广泛研究。这些研究比较了参与多环芳烃代谢的基因多态性或不多态性的吸烟者的肺癌风险。我们相信，致癌物代谢物表型分析（涉及 PAH 代谢物的实际测量）将是研究肺癌风险差异的更好方法。考虑到这一目标，我们开发了定量尿液中菲代谢物的方法。菲是海湾地区最简单的多环芳烃，这一特征与致癌性密切相关。尿代谢物 r-1,t-2,3,c-4-四羟基-1,2,3,4-四氢菲 (PheT) 是代谢激活的指标，而菲酚 (HOPhe) 是解毒的指标。在这项研究中，我们量化了 346 名吸烟者的尿 PheT/HOPhe 比率，这些吸烟者还对参与 PAH 代谢的基因的 11 种多态性进行了基因分型：CYP1A1MspI、CYP1A1I462V、CYP1B1R48G、CYP1B1A119S、CYP1B1L432V、CYP1B1N453S、 EPHX1Y113H。 EPHX1H139R、GSTP1I105V、GSTP1A114V 和 GSTM1 无效。 PheT/3-HOPhe 的几何平均摩尔比为 4.08（95% 置信区间，3.79-4.39）。百分之十的吸烟者的 PheT/3-HOPhe 比率 >= 9.90。我们发现 CYP1A1I462V 多态性的存在与高 PheT/3-HOPhe 比率之间存在显着相关性 (P = 0.02)。这种效应在女性中尤其强烈，并且与 GSTM1 无效多态性相结合。相比之下，CYP1B1R48G 和 CYP1B1A119S 多态性与显着较低的 PheT/3-HOPhe 比率相关，特别是在黑人中。任何其他多态性对 PheT/3-HOPhe 比率没有一致的显着影响。最高 10% 的 PheT/3-HOPhe 比率无法通过 11 种多态性中的任何一种单独或某些组合的存在来预测。这里观察到的 CYP1A1I462 多态性的影响，特别是与 GSTM1 null 组合的影响，与文献中的报告非常一致。然而，这项研究的结果表明，基因分型并不是预测 PAH 代谢的有效方法，至少从 PheT/HOPhe 比率来看是这样。
The hypothesis that interindividual differences among smokers in the metabolism of polycyclic aromatic hydrocarbons (PAH) are related to lung cancer risk has been extensively investigated in the literature. These studies have compared lung cancer risk in groups of smokers with or without polymorphisms in genes involved in PAH metabolism. We believe that carcinogen metabolite phenotyping, involving the actual measurement of PAH metabolites, would be a better way to investigate differences in lung cancer risk. With this goal in mind, we have developed methods for quantifying phenanthrene metabolites in urine. Phenanthrene is the simplest PAH with a bay region, a feature closely associated with carcinogenicity. The urinary metabolite r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (PheT) is a measure of metabolic activation, whereas phenanthrols (HOPhe) are a measure of detoxification. In this study, we quantified urinary PheT/HOPhe ratios in 346 smokers who were also genotyped for 11 polymorphisms in genes involved in PAH metabolism: CYP1A1MspI, CYP1A1I462V, CYP1B1R48G, CYP1B1A119S, CYP1B1L432V, CYP1B1N453S, EPHX1Y113H. EPHX1H139R, GSTP1I105V, GSTP1A114V, and GSTM1 null. The geometric mean molar PheT/3-HOPhe ratio was 4.08 (95% confidence interval, 3.79-4.39). Ten percent of the smokers had PheT/3-HOPhe ratios of >= 9.90. We found a significant association between the presence of the CYP1A1I462V polymorphism and high PheT/3-HOPhe ratios (P = 0.02). This effect was particularly strong in females and in combination with the GSTM1 null polymorphism. In contrast, the CYP1B1R48G and CYP1B1A119S polymorphisms were associated with significantly lower PheT/3-HOPhe ratios, particularly in Blacks. There were no consistent significant effects of any of the other polymorphisms on PheT/3-HOPhe ratios. The highest 10% of PheT/3-HOPhe ratios could not be predicted by the presence of any of the 11 polymorphisms individually or by certain combinations. The effects of the CYP1A1I462 polymorphism observed here, particularly in combination with GSTM1 null, are quite consistent with reports in the literature. However, the results of this study indicate that genotyping is not an effective way to predict PAH metabolism at least as represented by PheT/HOPhe ratios.