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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Susceptibility to hepatocellular carcinoma is associated with genetic variation in the enzymatic detoxification of aflatoxin B1.
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Susceptibility to hepatocellular carcinoma is associated with genetic variation in the enzymatic detoxification of aflatoxin B1.

机译：肝细胞癌的易感性与黄曲霉毒素B1酶解毒中的遗传变异有关。

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摘要

Aflatoxin B1 (AFB1) has been postulated to be a hepatocarcinogen in humans, possibly by causing p53 mutations at codon 249. AFB1 is metabolized via the phase I and II detoxification pathways; hence, genetic variation at those loci may predict susceptibility to the effects of AFB1. To test this hypothesis, genetic variation in two AFB1 detoxification genes, epoxide hydrolase (EPHX) and glutathione S-transferase M1 (GSTM1), was contrasted with the presence of serum AFB1-albumin adducts, the presence of hepatocellular carcinoma (HCC), and with p53 codon 249 mutations. Mutant alleles at both loci were significantly overrepresented in individuals with serum AFB1-albumin adducts in a cross-sectional study. Mutant alleles of EPHX were significantly overrepresented in persons with HCC, also in a case-control study. The relationship of EPHX to HCC varied by hepatitis B surface antigen status and indicated that a synergistic effect may exist. p53 codon 249 mutations were observed only among HCC patients with oneor both high-risk genotypes. These results indicate that individuals with mutant genotypes at EPHX and GSTM1 may be at greater risk of developing AFB1 adducts, p53 mutations, and HCC when exposed to AFB1. Hepatitis B carriers with the high-risk genotypes may be an even greater risk than carriers with low-risk genotypes. These findings support the existence of genetic susceptibility in humans to the environmental carcinogen AFB1 and indicate that there is a synergistic increase in risk of HCC with the combination of hepatitis B virus infection and susceptible genotype.
机译：黄曲霉毒素B1（AFB1）已被推测是人类肝癌，可能是通过在249位密码子处引起p53突变而引起的。AFB1是通过I和II期解毒途径代谢的。因此，这些位点的遗传变异可能预测对AFB1的敏感性。为了验证这一假设，我们将两种AFB1排毒基因，即环氧水解酶（EPHX）和谷胱甘肽S-转移酶M1（GSTM1）的遗传变异与血清AFB1-白蛋白加合物，肝细胞癌（HCC）和p53密码子249个突变。在一项横断面研究中，具有血清AFB1-白蛋白加合物的个体在两个基因座处的突变等位基因均明显超标。在病例对照研究中，在肝癌患者中EPHX的突变等位基因也明显过高。 EPHX与HCC的关系因乙型肝炎表面抗原状态而异，表明可能存在协同作用。仅在具有一种或两种高风险基因型的HCC患者中观察到p53密码子249突变。这些结果表明，在EPHX和GSTM1具有突变基因型的个体暴露于AFB1时，罹患AFB1加合物，p53突变和HCC的风险更大。具有高风险基因型的乙型肝炎携带者可能比具有低风险基因型的乙型肝炎携带者更大。这些发现支持人类对环境致癌物AFB1的遗传易感性存在，并表明与乙型肝炎病毒感染和易感基因型相结合，HCC风险协同增加。

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