Influence of DNA Repair on Nonlinear Dose-Responses for Mutation
Influence of DNA Repair on Nonlinear Dose-Responses for Mutation
复制标题
DNA 修复对突变非线性剂量反应的影响
作者：
Adam D. Thomas;G. Jenkins;B. Kaina;O. Bodger;Karl;P. Lewis;S. Doak;G. Johnson
最近的证据挑战了默认的假设，即所有dna反应性烷基化剂都表现出线性剂量反应。新出现的证据表明，模型烷基化剂甲基和乙基甲烷磺酸盐以及甲基亚硝基脲（MNU）和乙基亚硝基脲观察到非线性剂量反应，没有观察到遗传毒性效应水平（NOGEL）。后续的机制研究对于了解细胞耐受机制和此类nogel的生物学相关性至关重要。MNU是最具诱变性的简单烷基化合物之一。因此，了解突变诱导机制，在低剂量MNU处理后，优先考虑较弱的诱变烷基化剂。在这里，我们以比先前研究低10倍的浓度测试MNU，并报告了人类淋巴母细胞样细胞的NOGEL为0.0075µg/ml (72.8nM)，通过次黄嘌呤（鸟嘌呤）磷酸核糖基转移酶测定（OECD 476）进行量化。机制研究表明，NOGEL依赖于o6 -甲基鸟嘌呤（O6MeG）被自杀酶O6MeG- dna甲基转移酶（MGMT）修复。MGMT失活使细胞对mnu诱导的突变敏感，并使NOGEL在剂量轴上向左移动。
Recent evidence has challenged the default assumption that all DNA-reactive alkylating agents exhibit a linear dose-response. Emerging evidence suggests that the model alkylating agents methyl- and ethylmethanesulfonate and methylnitrosourea (MNU) and ethylnitrosourea observe a nonlinear dose-response with a no observed genotoxic effect level (NOGEL). Follow-up mechanistic studies are essential to understand the mechanism of cellular tolerance and biological relevance of such NOGELs. MNU is one of the most mutagenic simple alkylators. Therefore, understanding the mechanism of mutation induction, following low-dose MNU treatment, sets precedence for weaker mutagenic alkylating agents. Here, we tested MNU at 10-fold lower concentrations than a previous study and report a NOGEL of 0.0075 µg/ml (72.8nM) in human lymphoblastoid cells, quantified through the hypoxanthine (guanine) phosphoribosyltransferase assay (OECD 476). Mechanistic studies reveal that the NOGEL is dependent upon repair of O6-methylguanine (O6MeG) by the suicide enzyme O6MeG-DNA methyltransferase (MGMT). Inactivation of MGMT sensitizes cells to MNU-induced mutagenesis and shifts the NOGEL to the left on the dose axis.
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DOI：
10.1016/s0027-5107(00)00002-6
发表时间：
2000-03
期刊：
Mutation research
影响因子：
--
作者：
B. S. Shane;D.L Smith-Dunn;J. G. deBoer;B. W. Glickman;M.L Cunningham
通讯作者：
B. S. Shane;D.L Smith-Dunn;J. G. deBoer;B. W. Glickman;M.L Cunningham
影响因子：
11.2
作者：
Joyce Bos
通讯作者：
Joyce Bos
影响因子：
4.7
作者：
Bernd Kaina;Gerhard Fritz;Sankar Mitra;T. Coquerelle
通讯作者：
Bernd Kaina;Gerhard Fritz;Sankar Mitra;T. Coquerelle
影响因子：
11.2
作者：
Istvan Boldogh;C. Ramana;C. Ramana;Zhenping Chen;Tapan Biswas;T. Hazra;Sabine Grösch;T. Grombacher;Sankar Mitra;Bernd Kaina
通讯作者：
Istvan Boldogh;C. Ramana;C. Ramana;Zhenping Chen;Tapan Biswas;T. Hazra;Sabine Grösch;T. Grombacher;Sankar Mitra;Bernd Kaina
影响因子：
4.7
作者：
JACOBY, RF;ALEXANDER, RJ;BRASITUS, TA
通讯作者：
BRASITUS, TA