期刊
CHEMICAL RESEARCH IN TOXICOLOGY
卷 18, 期 11, 页码 1683-1690出版社
AMER CHEMICAL SOC
DOI: 10.1021/tx0500528
关键词
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资金
- NIEHS NIH HHS [ES05355, P30ES0676] Funding Source: Medline
Acrolein-derived DNA adducts of guanine have previously been detected in tissues of several species, including humans, and have been shown to be mutagenic in mammalian cells and potentially carcinogenic in higher organisms. In duplex DNA, the predominant acrolein-derived lesion, gamma-hydroxy-1,N-2-propanodeoxyguanosine (gamma-HOPdG), exists in an equilibrated mixture of ring-opened and ring-closed forms. We have previously shown that the acyclic form can undergo secondary chemical reactions to form both interstrand DNA-DNA cross-links in a CpG sequence context and DNA-protein and DNA-peptide cross-links. Investigations using duplex DNAs containing gamma-HOPdG in a CpG sequence context reversibly created at least two cross-linked species: an imine, which is a minor species but could be readily reduced by NaBH4, and a major heat labile, nonreducible species that we formulate as a carbinolamine cross-link. The DNA came to equilibrium over several days with the carbinolamine species being significantly more abundant than the reducible imine. In an effort to find other types of DNA-DNA cross-links, we have developed a high throughput screen to evaluate the effects of DNA sequence and lesion structure on the formation of reducible interstrand and intrastrand crosslinks. These data reveal that four different lesions, two involving deoxyguanosine and two involving deoxyadenosine, can react with nearby bases to form inter- and intrastrand DNA cross-links.
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