Genetic polymorphisms in heterocyclic amine metabolism and risk of colorectal adenomas
Genetic polymorphisms in heterocyclic amine metabolism and risk of colorectal adenomas
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DOI：
10.1097/00008571-200203000-00008
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发表时间：
2002-03-01
期刊：
影响因子：
--
通讯作者：
Rothman, N
中科院分区：
文献类型：
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作者：
Ishibe, N;Sinha, R;Rothman, N
大量红肉摄入与结直肠癌和腺瘤的风险增加有关。在红肉的高温烹饪过程中，会产生杂环胺（HCAs）;然而，要致癌，它们必须被包括细胞色素P450 1A 2（CYP 1A 2）和N-乙酰转移酶1（NAT 1）和/或N-乙酰转移酶2（NAT 2）在内的酶代谢。我们进行了一项以临床为基础的结直肠腺瘤病例对照研究，重点是评估HCA暴露（通过使用HCA数据库和肉类烹饪模块估计）和遗传因素对这些暴露的影响。我们以前曾报道过，MelQx的摄入与结直肠腺瘤风险增加相关[在第80百分位数，> 27.00 ng/天：比值比（OR）= 2.68，95%置信区间（CI）1.58-4.55]。在这里，我们报告了我们的评估是否在CYP 1A 2，NAT 1和/或NAT 2的变化修改之间的关联HCAs和结直肠腺瘤形成146例和228频率匹配的对照。NAT 1 * 10等位基因与结直肠腺瘤风险增加无显著性相关（OR = 1.43; 95%CI 0.86-2.36）。此外，当我们分析2-氨基-3，8-二甲基咪唑[4，5-f]喹喔啉（MelQx）摄入量作为分类变量时，我们观察到每天摄入超过27 ng的快速NAT 1乙酰化者的腺瘤风险增加了6倍（OR = 6.50; 95%CI 2.16-19.7），而在缓慢的NAT 1乙酰化者中，风险增加两倍（OR = 2.32; 95%CI 1.12-4.81）。虽然具有提示性，但结果在加法或乘法尺度上彼此之间没有显著差异。相比之下，NAT 2基因型和咖啡因尿代谢产物测定的CYP 1A 2和NAT 2肝活性与腺瘤风险无关，尽管不能排除CYP 1A 2快速活性增加的风险（OR = 1.46; 95%CI 0.76-2.81）。此外，没有证据表明MeIQx的作用在任何亚组中的受试者中增强，这些亚组由这些指标的变化定义。这些结果与高HCA暴露与结直肠腺瘤风险增加相关的假设一致，特别是在遗传易感亚组中。需要对更大的人群进行进一步研究，以证实和扩展这些观察结果。
High red meat intake has been linked with an increased risk of colorectal cancer and adenomas. During high temperature cooking of red meats, heterocyclic amines (HCAs) are generated; however, to be carcinogenic, they must be metabolized by enzymes including cytochrome P450 1A2 (CYP1A2) and N-acetyltransferase 1 (NAT1) and/or N-acetyltransferase 2 (NAT2). We have conducted a clinic-based case-control study of colorectal adenomas that focused on assessment of exposure to HCAs (estimated by use of a HCA database and meat cooking module) and modification of these exposures by genetic factors. We have previously reported that intake of MelQx was associated with an increased risk of colorectal adenomas [overall association at 80th percentile, > 27.00 ng/day: odds ratio (OR) = 2.68,95% confidence interval (CI) 1.58-4.55]. Here, we report our evaluation of whether variation in CYP1A2, NAT1 and/or NAT2 modify the association between HCAs and colorectal adenoma formation in 146 cases and 228 frequency-matched controls. The NAT1* 10 allele was associated with a nonsignificant increased risk of colorectal adenomas (OR = 1.43; 95% Cl 0.86-2.36). Further, when we analysed 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MelQx) intake as a categorical variable, we observed a six-fold increase in adenoma risk among rapid NAT1 acetylators who consumed more than 27 ng a day (OR = 6.50; 95% Cl 2.16-19.7), whereas among slow NAT1 acetylators, the increase in risk was two-fold (OR = 2.32; 95% Cl 1.12-4.81). While suggestive, the results were not significantly different from each other on either an additive or multiplicative scale. In contrast, NAT2 genotype and CYP1A2 and NAT2 hepatic activity measured by caffeine urinary metabolites were not associated with adenoma risk, although an increase in risk with rapid CYP1A2 activity could not be ruled out (OR = 1.46; 95% Cl 0.76-2.81). Moreover, there was no evidence that the effect of MeIQx was enhanced among subjects in any subgroup defined by variation in these measures. These results are compatible with the hypothesis that high HCA exposure is associated with an increased risk of colorectal adenomas, particularly in genetically susceptible subgroups. Further study of larger populations is needed to confirm and extend these observations.