The role of human glutathione S-transferases (hGSTs) in the detoxification of the food-derived carcinogen metabolite N-acetoxy-PhIP, and the effect of a polymorphism in hGSTA1 on colorectal cancer risk
The role of human glutathione S-transferases (hGSTs) in the detoxification of the food-derived carcinogen metabolite N-acetoxy-PhIP, and the effect of a polymorphism in hGSTA1 on colorectal cancer risk
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DOI：
10.1016/s0027-5107(01)00187-7
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发表时间：
2001-10-01
影响因子：
2.3
通讯作者：
Kadlubar, FF
中科院分区：
文献类型：
--
作者：
Coles, B;Nowell, SA;Kadlubar, FF
食源性杂环胺（HCAs），特别是2-氨基-1-甲基-6-苯基咪唑并[4，5-B]吡啶（PhIP），通过N-氧化、O-乙酰化或O-硫酸化形成亲电代谢产物与DNA反应，参与了人类结直肠癌（CRC）的病因学。谷胱甘肽S-转移酶（GST）通过催化它们与GSH的反应来解毒活化的致癌物代谢物。然而，在HCA中，仅N-乙酰氧基-PhIP已被证明是GST的底物。通过使用竞争性DNA结合试验，我们确认hGSTA 1 -1是N-乙酰氧基-PhIP解毒的有效催化剂。此外，我们表明hGST A2-2、P1-1、M1-1、T1-1和T2-2似乎对N-乙酰氧基-PhIP具有低活性，并且hGST A4-4、M2-2、M4-4和Z1-1似乎对N-乙酰氧基-PhIP没有活性。hGSTA 1的5 ' -调控序列中的遗传多态性已显示与人肝脏中GSTA 1/GSTA 2的相对和绝对表达水平相关。在100例白种人CRC患者和226例白种人对照中检测hGSTA 1等位基因频率，结果显示与对照组相比，病例组中纯合hGSTA 1 *B基因型显著过多（分别为24.0%和13.7%，P = 0.04）。当将纯合hGSTA 1 *B个体与所有其他基因型进行比较时，这相当于CRC风险的比值比为2.0（95%CI 1.0-3.7）。因此。为纯合hGSTA 1 *B的个体，以及被预测在其肝脏中具有最低水平的hGSTA 1表达的个体，似乎处于发生CRC的风险中，这可能是N-乙酰氧基-PhIP的无效肝脏解毒的结果。(C)2001 Elsevier Science B. V.保留所有权利。
Food-derived heterocyclic amines (HCAs), particularly 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), are implicated in the etiology of human colorectal cancer (CRC) via a process of N-oxidation followed by O-acetylation or O-sulfation to form electrophilic metabolites that react with DNA. Glutathione S-transferases (GSTs) detoxify activated carcinogen metabolites by catalysis of their reaction with GSH. However, among HCAs, only N-acetoxy-PhIP has been shown to be a substrate for the GSTs. By using a competitive DNA-binding assay, we confirm that hGSTA1-1 is an efficient catalyst of the detoxification of N-acetoxy-PhIP. Further, we show that hGSTs A2-2, P1-1, M1-1, T1-1 and T2-2 appear to have low activity towards N-acetoxy-PhIP, and that hGSTs A4-4, M2-2, M4-4 and Z1-1 appear to have no activity towards N-acetoxy-PhIP. A genetic polymorphism in the 5 ' -regulatory sequence of hGSTA1 has been shown to correlate with the relative and absolute levels of expression of GSTA1/GSTA2 in human liver. Examination of hGSTA1 allele frequency in 100 Caucasian CRC patients and 226 Caucasian controls demonstrated a significant over-representation of the homozygous hGSTA1*B genotype among cases compared to controls (24.0 and 13.7%, respectively, P = 0.04). This corresponds to an odds ratio for risk of CRC of 2.0 (95% Cl 1.0-3.7) when comparing homozygous hGSTA1*B individuals with all other genotypes. Thus. individuals who are homozygous hGSTA1*B, and who would be predicted to have the lowest levels of hGSTA1 expression in their livers, appear to be at risk of developing CRC, possibly as a result of inefficient hepatic detoxification of N-acetoxy-PhIP. (C) 2001 Elsevier Science B.V. All rights reserved.