Dedon P C, Plastaras J P, Rouzer C A, Marnett L J
Division of Toxicology, Massachusetts Institute of Technology, 56-787, Cambridge, MA 02139, USA.
Proc Natl Acad Sci U S A. 1998 Sep 15;95(19):11113-6. doi: 10.1073/pnas.95.19.11113.
Oxidation of endogenous macromolecules can generate electrophiles capable of forming mutagenic adducts in DNA. The lipid peroxidation product malondialdehyde, for example, reacts with DNA to form M1G, the mutagenic pyrimidopurinone adduct of deoxyguanosine. In addition to free radical attack of lipids, DNA is also continuously subjected to oxidative damage. Among the products of oxidative DNA damage are base propenals. We hypothesized that these structural analogs of malondialdehyde would react with DNA to form M1G. Consistent with this hypothesis, we detected a dose-dependent increase in M1G in DNA treated with calicheamicin and bleomycin, oxidizing agents known to produce base propenal. The hypothesis was proven when we determined that 9-(3-oxoprop-1-enyl)adenine gives rise to the M1G adduct with greater efficiency than malondialdehyde itself. The reactivity of base propenals to form M1G and their presence in the target DNA suggest that base propenals derived from oxidative DNA damage may contribute to the mutagenic burden of a cell.
内源性大分子的氧化可产生能够在DNA中形成诱变加合物的亲电试剂。例如，脂质过氧化产物丙二醛与DNA反应形成M1G，即脱氧鸟苷的诱变嘧啶嘌呤酮加合物。除了脂质的自由基攻击外，DNA也不断受到氧化损伤。氧化DNA损伤的产物包括碱基丙烯醛。我们推测这些丙二醛的结构类似物会与DNA反应形成M1G。与这一假设一致，我们在用加利车霉素和博来霉素处理的DNA中检测到M1G呈剂量依赖性增加，这两种氧化剂已知会产生碱基丙烯醛。当我们确定9-(3-氧代丙-1-烯基)腺嘌呤比丙二醛本身更有效地产生M1G加合物时，这一假设得到了证实。碱基丙烯醛形成M1G的反应性及其在靶DNA中的存在表明，源自氧化DNA损伤的碱基丙烯醛可能会增加细胞的诱变负担。
