DNA adduct formation of 4-aminobiphenyl and heterocyclic aromatic amines in human hepatocytes.
DNA adduct formation of 4-aminobiphenyl and heterocyclic aromatic amines in human hepatocytes.
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DOI：
10.1021/tx200091y
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发表时间：
2011-06-20
影响因子：
4.1
通讯作者：
Turesky RJ
中科院分区：
文献类型：
--
作者：
Nauwelaers G;Bessette EE;Gu D;Tang Y;Rageul J;Fessard V;Yuan JM;Yu MC;Langouët S;Turesky RJ
芳香胺、4-氨基联苯 (4-ABP)（烟草烟雾中存在的已知人类致癌物）与杂环芳香胺 (HAAs)、2-氨基-9H-吡啶并[2,3-b]吲哚 (AαC)、2-氨基-1-甲基-6-苯基咪唑并[4,5-b]吡啶 (PhIP) 形成 DNA 加合物， 2-氨基-3-甲基咪唑[4,5-f]喹啉（IQ）和2-氨基-3,8-二甲基咪唑[4,5-f]喹喔啉（MeIQx）是潜在的人类致癌物，它们也存在于烟草烟雾中或在高温烹饪肉类过程中形成，在新鲜培养的人肝细胞中进行了研究。将致癌物 (10 μM) 与来自八个不同供体的肝细胞一起孵育长达 24 小时。 DNA加合物通过液相色谱-电喷雾电离质谱法和线性四极离子阱质谱仪进行定量。所有致癌物形成的主要 DNA 加合物是 N-(脱氧鸟苷-8-基) (dG-C8) 加合物。加合物的水平范围为每 107 个 DNA 碱基 3.4 至 140 个加合物。加合物形成水平最高的是 AαC，其次是 4-ABP，然后是 PhIP、MeIQx 和 IQ。人肝细胞形成的 dG-C8-HAA 加合物的水平比大鼠肝细胞中产生的加合物的量高出 100 倍。与 HAA 加合物相反，人和大鼠肝细胞中 dG-C8-4-ABP 加合物形成的水平相似。这些 DNA 结合数据表明，用于致癌生物测定的动物模型大鼠明显低估了 HAA 对人类的潜在肝脏遗传毒性。值得注意的是，AαC 形成的高水平 DNA 加合物是烟草烟雾中产生的致癌物质，其含量比 4-ABP 的含量高出 100 倍。 AαC 在烟草相关癌症中可能的因果作用值得研究。
DNA adduct formation of the aromatic amine, 4-aminobiphenyl (4-ABP), a known human carcinogen present in tobacco smoke, and the heterocyclic aromatic amines (HAAs), 2-amino-9H-pyrido[2,3-b]indole (AαC), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), and 2-amino-3,8-dimethylmidazo[4,5-f]quinoxaline (MeIQx), potential human carcinogens, which are also present in tobacco smoke or formed during the high-temperature cooking of meats, was investigated in freshly cultured human hepatocytes. The carcinogens (10 μM) were incubated with hepatocytes derived from eight different donors for time periods up to 24 h. The DNA adducts were quantified by liquid chromatography-electrospray ionization mass spectrometry with a linear quadrupole ion trap mass spectrometer. The principal DNA adducts formed for all of the carcinogens were N-(deoxyguanosin-8-yl) (dG-C8) adducts. The levels of adducts ranged from 3.4 to 140 adducts per 107 DNA bases. The highest level of adduct formation occurred with AαC, followed by 4-ABP, then by PhIP, MeIQx, and IQ. Human hepatocytes formed dG-C8-HAA-adducts at levels that were up to 100-fold greater than the amounts of adducts produced in rat hepatocytes. In contrast to HAA adducts, the levels of dG-C8-4-ABP adduct formation were similar in human and rat hepatocytes. These DNA binding data demonstrate that the rat, an animal model that is used for carcinogenesis bioassays, significantly underestimates the potential hepatic genotoxicity of HAAs in humans. The high level of DNA adducts formed by AαC, a carcinogen produced in tobacco smoke at levels that are up to 100-fold higher than the amounts of 4-ABP, is noteworthy. The possible causal role of AαC in tobacco-associated cancers warrants investigation.
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影响因子：
3.8
作者：
Bendaly, Jean;Zhao, Shuang;Hein, David W.
通讯作者：
Hein, David W.
影响因子：
4.3
作者：
Frederiksen, H;Frandsen, H
通讯作者：
Frandsen, H
影响因子：
4.1
作者：
Garrigós, MC;Reche, F;Jiménez, A
通讯作者：
Jiménez, A
影响因子：
7.4
作者：
Gu, Dan;Raymundo, Melissa M.;Turesky, Robert J.
通讯作者：
Turesky, Robert J.
DOI：
10.1073/pnas.86.20.7696
发表时间：
1989-10-01
影响因子：
11.1
作者：
BUTLER, MA;IWASAKI, M;KADLUBAR, FF
通讯作者：
KADLUBAR, FF