異環胺暴露與N-乙烯基轉移酶基因多型性之於臺灣大腸癌風險初探

A Pilot Study of Heterocyclic Amines Exposure and N-Acetyltransferase Genetic Polymorphisms related to Colorectal Cancer Risk in Taiwan

盧恩萱(En-Hsuan Lu)

指導教授 ： 吳焜裕

國立臺灣大學/公共衛生學院/職業醫學與工業衛生研究所/碩士(2017年)

https://doi.org/10.6342/NTU201702331

摘要

大腸直腸癌發生率已連續八年高居臺灣十大癌症之首，發生率及死亡率逐年增加，文獻指出攝食高溫處理的紅肉與肉類加工產品所產生的異環胺為危險因子。N-乙醯基轉移酶參與異環胺在生物體內的代謝，進而影響DNA共價鍵結物生成。由於國人N-乙醯基轉移酶基因多型性與歐美人種不同，異環胺暴露對於國人產生的致癌風險無法一概而論，其真實致癌風險至今仍未有系統性研究。因此，本研究欲探討異環胺(IQ、MeIQ、MeIQx和PhIP)暴露、N-乙醯基轉移酶2(NAT2)之基因多型性與罹患大腸直腸癌的相關性。
本篇初探研究共收集臺大醫院及臺北榮民總醫院共65名大腸直腸癌病患與19名控制組病患，並利用高效液相層析串聯質譜儀建立異環胺於人體尿液中的分析方法，作為異環胺暴露的生物指標，亦收集血液以定序NAT2之基因多型性，並進行問卷調查受試者的飲食習慣與生活方式。
六個大腸癌尿液檢體偵測到小於定量極限的PhIP，檢出率為7.14%，快速/中代謝型與慢代謝型的NAT2在大腸癌病患中比例分別為72.13%與27.87%，在控制組病患中比例則分別為42.10%與57.90%，而臺灣族群主要攜帶快代謝型之NAT2*4基因，然而並未發現病患與控制組之間有顯著差異性。年齡為罹患大腸癌之干擾因子，高程度喜愛攝食火炒肉品者會比中/低程度喜愛火炒肉品者多2.04倍罹患大腸癌風險(95% 信賴區間: 0.65, 6.42)，然而未有統計上顯著差異性。
本研究建立同時偵測四種異環胺(IQ、MeIQ、MeIQx和PhIP)之高效液相層析串聯質譜儀分析方法，因樣本數限制無法鑑定NAT2基因多型性與大腸直腸癌之間的相關性，然而本研究發現臺灣人口傾向攜帶NAT2快速乙醯化基因型，與歐美人口基因分布不同。未來研究需要應用更先進之分析儀器以提高偵測靈敏度，並且需要藉由更長時間、收集更多病患來評估大腸癌致癌風險。

關鍵字

異環胺 ； 大腸直腸癌 ； N-乙醯基轉移酶 ； 高效液相層析串聯質譜儀

並列摘要

Colorectal cancer has dominated the top 10 cancer incidence list for eight years in Taiwan. Both incidence and death rates are on the rise. Previous studies indicated that exposure to heterocyclic amines (HCAs) formed from the consumption of high-temperature processed meat, including red and white meat, fish, and processed meat products could elevate the risks of colorectal cancer. N-acetyltransferase (NAT) acetylation is involved in the metabolism of HCAs, thus further affecting the formation of DNA adducts. Besides, Taiwanese NAT genetic polymorphisms are different from those of Europeans and Americans and may interact with HCAs exposure so as to lead to colorectal cancer development. Colorectal cancer risk has yet to be systematically investigated through measurement of NAT genetic polymorphisms and HCAs exposures. Thus, this study aims to clarify the relationship of HCAs (IQ, MeIQ, MeIQx, PhIP) exposure, NAT2 genetic polymorphisms and the development of colorectal cancer.
A total of 65 colorectal cancer patients and 19 controls in National Taiwan University Hospital and Taipei Veterans General Hospital were recruited in this pilot study. A high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method was developed to measure urinary HCAs parent compounds which served as biomarkers for HCAs exposures. Human blood was genotyped to denote NAT2 genetic polymorphisms. Dietary habits and lifestyles variables were collected by using questionnaires.
Low concentrations of PhIP (below LOQ) were detected in six urine samples, which resulted in 7.14% of detectable rates. The rapid/intermediate genotype and slow genotype of NAT2 in colorectal cancer patients were found to be 72.13% and 27.87% respectively, while in controls were 42.10% and 57.90% respectively. The fast NAT2*4 haplotype dominates in Taiwanese population. However, no statistical difference was found in NAT2 acetylator genotypes among cases and controls. Age was a confounding factor of risk of colorectal cancer. High preference of pan-fried showed increased 2.04-fold of odds ratio (95% CI: 0.65, 6.42) compared with low/medium preference, although no statistically significant association existed.
This study demonstrated the HPLC-MS/MS method as to determine four HCA compounds (IQ, MeIQ, MeIQx, PhIP) in urine simultaneously. Limited numbers of study subjects were not able to identify the association between NAT2 genetic polymorphisms and colorectal cancer risk. However, this study still found that Taiwanese population tends to possess fast NAT2 acetylator genotype, which differs from the distributions of Europeans and Americans. Further research needs to improve the sensitivity of the method by using more advanced instrument. The results need to be confirmed with longer and larger recruitment of participants as to assess the risk of colorectal cancer.

並列關鍵字

Heterocyclic amine ； Colorectal cancer ； N-acetyltransferase ； HPLC-MS/MS

參考文獻

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