DISSOCIATION OF MALONDIALDEHYDE MUTAGENICITY IN SALMONELLA-TYPHIMURIUM FROM ITS ABILITY TO INDUCE INTERSTRAND DNA CROSS-LINKS
DISSOCIATION OF MALONDIALDEHYDE MUTAGENICITY IN SALMONELLA-TYPHIMURIUM FROM ITS ABILITY TO INDUCE INTERSTRAND DNA CROSS-LINKS
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DOI：
10.1016/0027-5107(84)90121-0
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发表时间：
1984-01-01
期刊：
影响因子：
--
通讯作者：
ROMANO, LJ
中科院分区：
文献类型：
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作者：
BASU, AK;MARNETT, LJ;ROMANO, LJ
丙二醛（MDA）是体内脂质过氧化和前列腺素生物合成的代谢产物，在S.鼠伤寒。它是一种反应性亲电试剂，可以在DNA中形成链间交联。为了探讨MDA诱导的链间交联是预致突变损伤的可能性，对高度纯化的MDA制剂与线性质粒DNA反应时形成链间交联的能力进行了定量。在生理温度和pH值下，MDA没有形成DNA交联，通过DNA变性，然后通过琼脂糖凝胶电泳确定。当与MDA在pH4.2或超过60 ℃的温度下进行温育时，形成DNA交联。α-甲基丙二醛（CH 3 MDA）被发现交联DNA比MDA更有效，但在任何沙门氏菌试验菌株中没有致突变性。MDA聚合物，形成酸孵育的MDA，也能够诱导交联。观察到致突变性和聚合程度之间呈反比关系。在不同的沙门氏菌菌株的MDA的致突变反应的模式进行了比较与丝裂霉素C，一个既定的致突变交联剂。错误倾向的修复和UvrB+表型，这是需要诱导突变的丝裂霉素C，不需要MDA诱变。这些发现结合在一起，将MDA的致突变性与其与DNA形成链间交联的能力分离。
Malondialdehyde (MDA), an in vivo metabolite of lipid peroxidation and prostaglandin biosynthesis, is mutagenic in S. typhimurium. It is a reactive electrophile that can form interstrand cross-links in DNA. To explore the possibility that MDA-induced interstrand cross-links are the pre-mutagenic lesion, the ability of highly purified preparations of MDA to form interstrand cross-links when reacted with linear plasmid DNA was quantitated. At physiological temperature and pH, MDA did not form DNA cross-links as determined by DNA denaturation followed by agarose gel electrophoresis. DNA cross-links were formed when incubations with MDA were carried out at either pH 4.2 or temperatures exceeding 60.degree.. .alpha.-Methylmalondialdehyde (CH3MDA) was found to cross-link DNA more efficiently than MDA, but was not mutagenic in any tester strain of Salmonella. MDA polymers, formed by acid incubation of MDA, also were capable of inducing cross-links. An inverse relationship was observed between mutagenicity and extent of polymerization. The pattern of mutagenic response for MDA in different strains of Salmonella was compared with mitomycin C, an established mutagenic cross-linking agent. Error-prone repair and a UvrB+ phenotype, which are needed for the induction of mutations by mitomycin C, were not required for MDA mutagenesis. These findings, taken together, dissociate the mutagenicity of MDA from its ability to form interstrand cross-links with DNA.