Synthesis, characterization, and mutagenicity of nitrated 7H-dibenzo[c,g]carbazole and its phenolic derivatives.
Synthesis, characterization, and mutagenicity of nitrated 7H-dibenzo[c,g]carbazole and its phenolic derivatives.
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硝化 7H-二苯并[c,g]咔唑及其酚类衍生物的合成、表征和致突变性。
DOI：
10.1021/tx960175f
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发表时间：
1997
期刊：
影响因子：
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通讯作者：
Warshawsky,D
中科院分区：
文献类型：
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作者：
Xue,W;LaDow,K;Warshawsky,D
硝化N-杂环芳烃（NAH）存在于各种环境来源中，其中许多已被确定为在短期试验中具有致突变性和/或在动物试验中具有致癌性。在本实验室中，我们合成和表征硝化7 H-二苯并[c，g]咔唑（DBC）和DBC的硝基酚代谢产物作为潜在的诱变和致癌的外源性物质。硝基仅在DBC、2-羟基-DBC、3-羟基-DBC和4-羟基-DBC的5位和/或对称9位形成。使用鼠伤寒沙门氏菌菌株TA 98和TA 100进行艾姆斯平板掺入致突变试验，加或不加大鼠肝匀浆（S9）。在菌株TA 98中，硝化DBC的致突变性高于亲本DBC。在所有试验中，5，9-二硝基-DBC的致突变反应均强于5-硝基-DBC，尤其是在含S9的菌株TA 98中。5，9-二硝基-DBC相对于5-硝基-DBC具有更高的还原电位（分别为-1.09 V和-1.37 V）。通过硝化相应的羟基-DBC合成的5-硝基-DBC在2、3、4、10或12位的羟基衍生物具有比亲本5-硝基-DBC更大的致突变性，尤其是在有或无S9的菌株TA 100中。我们的数据表明，硝化DBC经历硝基还原和环氧化作为代谢活化的主要途径，导致诱变。硝基-羟基-DBC异构体的相对致突变性通常与硝基官能团形成的芳基氮鎓离子上正电荷的共振稳定性一致，作为拟定的活性亲电试剂，负责遗传毒性效应。
The nitrated N-heterocyclic aromatic hydrocarbons (NAHs) are found in a variety of environmental sources; many of them have been determined to be mutagenic in short-term assays and/or carcinogenic in animal tests. In this laboratory, we synthesized and characterized nitrated 7H-dibenzo[c,g]carbazole (DBC) and the nitrophenolic metabolites of DBC as potential mutagenic and carcinogenic xenobiotics. The nitro group was formed exclusively at the 5 and/or the symmetric 9 position of DBC, 2-hydroxy-DBC, 3-hydroxy-DBC, and 4-hydroxy-DBC. Ames plate incorporation mutagenicity assays were conducted usingSalmonella typhimuriumstrains TA98 and TA100, with or without rat liver homogenates (S9). Mutagenicities of the nitrated DBCs were higher than the parent DBC in strain TA98. 5,9-Dinitro-DBC had stronger mutagenic responses than 5-nitro-DBC in all assays, particularly in strain TA98 with S9. 5,9-Dinitro-DBC had a higher reduction potential relative to 5-nitro-DBC (−1.09 V and −1.37 V, respectively). Hydroxyl derivatives of 5-nitro-DBC at the 2, 3, 4, 10, or 12 position, synthesized through nitration of the corresponding hydroxy-DBC, possessed greater mutagenicity than the parent 5-nitro-DBC, especially in strain TA100 with or without S9. Our data suggest that nitrated DBC undergoes both nitroreduction and ring oxidation as the primary pathways for the metabolic activation leading to mutagenesis. The relative mutagenicities of the nitro-hydroxy-DBC isomers are generally consistent with the resonance stabilization of the positive charge at the arylnitrenium ion, formed from the nitro functional group, as the proposed active electrophile responsible for genotoxic effects.