Mutational Spectrum and Genotoxicity of the Major Lipid Peroxidation Product, trans-4-Hydroxy-2-nonenal, Induced DNA Adducts in Nucleotide Excision Repair-Proficient and -Deficient Human Cells
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- 作者：Zhaohui Feng ; Wenwei Hu ; Shantu Amin ; and Moon-shong Tang
- 刊名：Biochemistry
- 出版年：2003
- 出版时间：July 1, 2003
- 年：2003
- 卷：42
- 期：25
- 页码：7848 - 7854
- 全文大小：95K
- 年卷期：v.42,no.25(July 1, 2003)
- ISSN：1520-4995
文摘
trans-4-Hydroxy-2-nonenal (4-HNE), a major product of lipid peroxidation, is able to interactwith DNA to form 6-(1-hydroxyhexanyl)-8-hydroxy-1,N2-propano-2'-deoxyguanosine (4-HNE-dG)adducts, but its genotoxicity and mutagenicity remain elusive. It has been reported that 4-HNE treatmentin human cells induces a high frequency of G·C to T·A mutations at the third base of codon 249 (AGG*)of the p53 gene, a mutational hot spot in human cancers, particularly in hepatocellular carcinoma. ThisG·C to T·A transversion at codon 249, however, has been thought to be caused by etheno-DNA adductsinduced by the endogenous metabolite of 4-HNE, 2,3-epoxy-4-hydroxynonanal. We have recently foundthat 4-HNE preferentially forms 4-HNE-dG adducts at the GAGG*C/A sequence in the p53 gene includingcodon 249 (GAGG*C). Our finding supports the possibility that G·C to T·A mutations at codon 249 maybe induced by 4-HNE-dG adducts. To investigate this possibility, we determined the mutational spectruminduced by 4-HNE-dG adducts in the supF gene of shuttle vector pSP189 replicated in human cells. Wehave found that 4-HNE-dG adducts are mutagenic and genotoxic in human cells, and that G·C to T·Atransversions are the most prevalent mutations induced by 4-HNE-dG adducts. Furthermore, 4-HNE-dG adducts induce a significantly higher level of genotoxicity and mutagenicity in nucleotide excisionrepair (NER)-deficient human and Escherichia coli cells than in NER-proficient cells, indicating thatNER is a major pathway for repairing 4-HNE-dG adducts in both human and E. coli cells. Together,these results suggest that 4-HNE-dG adducts may contribute greatly to the G·C to T·A mutation atcodon 249 of the p53 gene, and may play an important role in carcinogenesis.