The aflatoxin B1 formamidopyrimidine adduct plays a major role in causing the types of mutations observed in human hepatocellular carcinoma
The aflatoxin B1 formamidopyrimidine adduct plays a major role in causing the types of mutations observed in human hepatocellular carcinoma
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DOI：
10.1073/pnas.102167699
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发表时间：
2002-05-14
影响因子：
11.1
通讯作者：
Essigmann, JM
中科院分区：
文献类型：
--
作者：
Smela, ME;Hamm, ML;Essigmann, JM
在超过50%的与高暴露于黄曲霉毒素B相关的肝细胞癌病例中，观察到p53肿瘤抑制基因密码子249的第三位发生G至T突变（AF B（1））。有人提出假设，AFB（1）与B肝炎病毒（HBV）一起可能在这种突变的形成和/或选择中发挥作用。AF B（1）的主要DNA加合物是8，9-二氢-8-（N-7-鸟苷基）-9-羟基黄曲霉毒素B-1（AF B（1）-N7-Gua），其自然转化为两个继发性损伤，脱嘌呤位点和AF B（1）-甲酰氨基嘧啶（AF B（1）-FAPY）加合物。AFB（1）-FAPY在暴露于AFB（1）后数天至数周在大鼠DNA中检测到接近最大水平，强调其在体内的高持久性。本研究揭示了这种DNA加合物的两个显著特性：（i）发现AFB（1）-FAPY在大肠杆菌中引起的G至T突变频率比AFB（1）-N7-Gua高约6倍，（ii）AFB（1）-FAPY的一种拟议旋转异构体是复制的阻滞剂，即使当细胞使用有效的旁路聚合酶MucAB时。总之，这些特性使FAPY加合物成为黄曲霉毒素遗传毒性的主要候选物，因为哺乳动物细胞也具有类似的对抗DNA损伤的旁路机制，以及最终可能导致肝癌的致突变性。
A G to T mutation has been observed at the third position of codon 249 of the p53 tumor-suppressor gene in over 50% of the hepatocellular carcinoma cases associated with high exposure to aflatoxin B, (AFB(1)). Hypotheses have been put forth that AFB(1), in concert with hepatitis B virus (HBV), may play a role in the formation of, and/or the selection for, this mutation. The primary DNA adduct of AFB(1) is 8,9-dihydro-8-(N-7-guanyl)-9-hydroxyafla-toxin B-1 (AFB(1)-N7-Gua), which is converted naturally to two secondary lesions, an apurinic site and an AFB(1)-formamidopyrimidine (AFB(1)-FAPY) adduct. AFB(1)-FAPY is detected at near maximal levels in rat DNA days to weeks after AFB(1) exposure, underscoring its high persistence in vivo. The present study reveals two striking properties of this DNA adduct: (i) AFB(1)-FAPY was found to cause a G to T mutation frequency in Escherichia coli approximately 6 times higher than that of AFB(1)-N7-Gua, and (ii) one proposed rotamer of AFB(1)-FAPY is a block to replication, even when the efficient bypass polymerase MucAB is used by the cell. Taken together, these characteristics make the FAPY adduct the prime candidate for both the genotoxicity of aflatoxin, because mammalian cells also have similar bypass mechanisms for combating DNA damage, and the mutagenicity that ultimately may lead to liver cancer.