Shelton M L, Ashby J, DeMarini D M
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711.
Mutat Res. 1994 Jan-Feb;323(1-2):35-9. doi: 10.1016/0165-7992(94)90042-6.
Methapyrilene (MP) is a rat-liver carcinogen and cocarcinogen that exhibits a narrow spectrum of mutagenic activity in Salmonella typhimurium, inducing only a 2-fold increase in revertants only in the base-substitution strain TA1535; it also enhances the mutagenic activity of sodium azide (NaN3) in the same strain. To examine the effects of MP at the molecular level, we used the colony probe hybridization procedure developed by Cebula and Koch (Mutation Res., 229 (1990) 79-87) to identify the base substitutions in approximately 800 background, MP-, NaN3-, and MP + NaN3-induced revertants of the hisG46 allele of strain TA1535. The predominant mutation in all 4 mutation spectra was a CCC-->CTC transition. The results suggest a mechanism by which MP enhances the infidelity of the DNA replication complex or inhibits a DNA repair or proofreading function, resulting in the production of more of the same error that occurs normally and that is also induced by NaN3. Such a mechanism might be the basis for the carcinogenic and cocarcinogenic activities of MP. To our knowledge, this is the first report of the molecular analysis of mutants produced by exposure of cells to a binary mixture of mutagens.
甲吡咯烷（MP）是一种大鼠肝脏致癌物和促癌剂，在鼠伤寒沙门氏菌中表现出狭窄的诱变活性谱，仅在碱基取代菌株TA1535中使回复突变体增加2倍；它还增强了同一菌株中叠氮化钠（NaN3）的诱变活性。为了在分子水平上研究MP的作用，我们使用了Cebula和Koch开发的菌落探针杂交程序（《突变研究》，229（1990）79 - 87）来鉴定在菌株TA1535的hisG46等位基因的大约800个背景、MP、NaN3和MP + NaN3诱导的回复突变体中的碱基取代。在所有4种突变谱中，主要的突变是CCC→CTC转换。结果表明了一种机制，通过该机制MP增强了DNA复制复合体的错误倾向或抑制了DNA修复或校对功能，导致产生更多与正常发生的以及由NaN3诱导的相同错误。这样一种机制可能是MP致癌和促癌活性的基础。据我们所知，这是关于细胞暴露于诱变剂二元混合物产生的突变体的分子分析的首次报告。
