Carcinogenic 3-nitrobenzanthrone induces oxidative damage to isolated and cellular DNA
Carcinogenic 3-nitrobenzanthrone induces oxidative damage to isolated and cellular DNA
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DOI：
10.1016/j.freeradbiomed.2005.11.015
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发表时间：
2006-04-01
影响因子：
7.4
通讯作者：
Kawanishi, S
中科院分区：
文献类型：
--
作者：
Murata, M;Tezuka, T;Kawanishi, S
3-硝基苯蒽酮（3-NBA）是柴油机尾气中一种极强的诱变剂。它是一种大鼠肺癌致癌物，因此是一种疑似人类致癌物。为了阐明3-NBA的致癌机制，我们用32 P标记的人抑癌基因p53 DNA片段研究了3-NBA代谢产物N-羟基-3-氨基苯并蒽酮（N-OH-阿坝）对DNA的氧化损伤作用。N-OH-阿坝引起Cu（II）介导的DNA损伤，内源性还原剂NADH显著增强了这一过程。过氧化氢酶和Cu（I）特异性螯合剂降低了DNA损伤，表明过氧化氢（H2 O2）和Cu（I）参与其中。N-OH-阿坝诱导的DNA损伤ACG序列的胞嘧啶和鸟嘌呤残基互补的密码子273，一个众所周知的热点的p53基因。在Cu（II）和NADH存在下，N-OH-阿坝剂量依赖性地诱导8-oxo-7，8-dihydro-2-deoxyguanosine（8-oxodG）的形成。与H2 O2抗性克隆HP 100相比，用N-OH-阿坝处理增加了HL-60细胞中8-oxodG的量，支持H2 O2的参与。本研究表明，3-NBA的N-羟基代谢产物通过H2 O2在无细胞系统和培养的人细胞中诱导氧化性DNA损伤。我们的结论是，氧化性DNA损伤可能发挥重要作用的致癌过程中3-NBA除了以前报道的DNA加合物fort-nation。(c)2005年爱思唯尔公司All rights reserved.
3-Nitrobenzanthrone (3-NBA) is an extremely potent mutagen in diesel exhaust. It is a lung carcinogen to rats, and therefore a suspected carcinogen to human. In order to clarify the mechanism of carcinogenicity of 3-NBA, we investigated oxidative DNA damage by N-hydroxy-3-aminobenzanthrone (N-OH-ABA), a metabolite of 3-NBA, using 32 P-labeled DNA fragments from the human p53 tumor-suppressor gene. N-OH-ABA caused Cu(II)-mediated DNA damage, and endogenous reductant NADH dramatically enhanced this process. Catalase and a Cu(I)-specific chelator decreased DNA damage, suggesting the involvement of hydrogen peroxide (H2O2) and Cu(I). N-OH-ABA induced DNA damage at cytosine and guanine residues of ACG sequence complementary to codon 273, a well-known hot spot of the p53 gene. N-OH-ABA dose dependently induced 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxodG) formation in the presence of Cu(II) and NADH. Treatment with N-OH-ABA increased amounts of 8-oxodG in HL-60 cells compared to the H2O2-resistant clone HP100, supporting the involvement of H2O2. The present study has demonstrated that the N-hydroxy metabolite of 3-NBA induces oxidative DNA damage through H2O2 in both a cell-free system and cultured human cells. We conclude that oxidative DNA damage may play an important role in the carcinogenic process of 3-NBA in addition to previously reported DNA adduct fort-nation. (c) 2005 Elsevier Inc. All rights reserved.