Mutagenesis associated with nitric oxide production in transgenic SJL mice
Mutagenesis associated with nitric oxide production in transgenic SJL mice
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DOI：
10.1073/pnas.93.26.15102
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发表时间：
1996-12-24
影响因子：
11.1
通讯作者：
Wogan, GN
中科院分区：
文献类型：
--
作者：
Gal, A;Wogan, GN
我们最近报道了一种用于研究一氧化氮（NO）的实验模式的发展。体内毒理学给SJL小鼠注射携带超抗原的RcsX（前B细胞淋巴瘤）细胞，其迁移到脾和淋巴结，在那里它们的快速生长诱导巨噬细胞活化，从而在几周的时间内产生大量的NO。在这里描述的实验中，我们使用该模型来研究在RcsX细胞生长期间暴露于NO的脾细胞中的诱变。通过将pUR 288转基因C57 BL/6和SJL品系的动物杂交产生转基因小鼠，将RcsX细胞注射到F-1小鼠中，并且通过定量尿硝酸盐（NO的最终代谢物）来证实NO的产生。在从脾（靶）和肾分离的DNA中测定pUR 288质粒的lacZ gent中的突变频率在荷瘤小鼠的脾脏中发现了突变频率的显著升高，但在肾脏中没有发现。此外，施用N-甲基精氨酸（一种NO抑制剂）可以消除香料中突变频率的增加以及NO产生，这些结果表明NO.在RcsX荷瘤小鼠中具有致突变活性，从而支持其参与致癌过程的可能作用。
We recently reported development of an experimental modes for the study of nitric oxide (NO.) toxicology in vivo. SJL mice were injected with superantigen-bearing RcsX (pre-B-cell lymphoma) cells, which migrated to the spleen and lymph nodes, where their rapid growth induced activation of macrophages etr produce large amounts of NO. over a period of sever al weeks. In the experiments described here, we used this model to investigate mutagenesis in splenocytes exposed to NO. during RcsX cell growth. Transgenic mice were produced by crossbreeding animals of the pUR288 transgenic C57BL/6 and SJL strains, RcsX cells were injected Into F-1 mice and NO. production mas confirmed by quantification of urinary nitrate, the ultimate metabolite of NO.. Mutant frequency in the lacZ gent of the pUR288 plasmid was determined in DNA isolated, from spleen (target) and kidney (nontarget) tissues, A significant elevation In mutant frequency mas found in the spleen, but not in the kidney, of tumor-bearing mice, Furthermore, increases in mutant frequency In the spices as well as NO. production were abrogated by administration of N-methylarginine, a NO. inhibitor, to mice following injection of RcsX cells, These results indicate that NO. had mutagenic activity in RcsX tumor-bearing mice and thus support a possible role fill its involvement in the carcinogenic process.