Malondialdehyde, a product of lipid peroxidation, is mutagenic in human cells

被引:433
作者
Niedernhofer, LJ
Daniels, JS
Rouzer, CA
Greene, RE
Marnett, LJ
机构
[1] Vanderbilt Univ, Sch Med,AB Hancock Jr Mem Lab Canc Res, Vanderbilt Inst Chem Biol,Dept Biochem, Vanderbilt Ingram Comprehens Canc Ctr, Nashville, TN 37232 USA
[2] Vanderbilt Univ, Sch Med, Vanderbilt Inst Chem Biol,Dept Chem, Vanderbilt Ingram Comprehens Canc Ctr, Nashville, TN 37232 USA
关键词
D O I
10.1074/jbc.M212549200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Malondialdehyde (MDA) is an endogenous genotoxic product of enzymatic and oxygen radical-induced lipid peroxidation whose adducts are known to exist in DNA isolated from healthy human beings. To evaluate the mutagenic potential of MDA in human cells, we reacted MDA with pSP189 shuttle vector DNA and then transfected them into human fibroblasts for replication. MDA induced up to a 15-fold increase in mutation frequency in the supF reporter gene compared with untreated DNA. Sequence analysis revealed that the majority of MDA-induced mutations occurred at GC base pairs. The most frequent mutations were large insertions and deletions, but base pair substitutions were also detected. MDA-induced mutations were completely abolished when the adducted shuttle vector was replicated in cells lacking nucleotide excision repair. MDA induction of large deletions and the apparent requirement for nucleotide excision repair suggested the possible involvement of a DNA interstrand cross-link as a premutagenic lesion. Indeed, MDA formed interstrand cross-links in duplex plasmids and oligonucleotides. Substrates containing the sequence 5'-d(CG) were preferentially crosslinked, consistent with the observation of base pair substitutions in 5'-d( CG) sites in the MDA-induced mutation spectrum. These experiments provide biological and biochemical evidence for the existence of MDA-induced DNA interstrand cross-links that could result from endogenous oxidative stress and likely have potent biological effects.
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收藏
页码:31426 / 31433
页数:8
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