Blair I A
Center for Cancer Pharmacology, University of Pennsylvania, 1254 BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA.
Exp Gerontol. 2001 Sep;36(9):1473-81. doi: 10.1016/s0531-5565(01)00133-4.
Lipid hydroperoxides are formed in vivo through free radical pathways from the action of reactive oxygen species on polyunsaturated fatty acids. They are also formed as specific products of lipoxygenases and cyclooxygenases. Homolytic decomposition of lipid hydroperoxides to the alpha,beta-unsaturated aldehyde genotoxins, 4-oxo-2-nonenal, 4,5-epoxy-2(E)-decenal, and 4-hydroxy-2-nonenal occurs through two quite distinct pathways. One pathway involves a complex rearrangement of the alkoxy radical derived from the lipid hydroperoxide and the other pathway involves the intermediate formation of another potential genotoxin, 4-hydroperoxy-2-nonenal. 4,5-Epoxy-2(E)-decenal forms the unsubstituted etheno-2-deoxyadenosine adduct with DNA, a mutagenic lesion which has been observed in human tissue DNA samples. Several new ethano- and etheno-DNA-adducts have been identified from the reaction of 4-oxo-2-nonenal with DNA. 4-Hydroxy-2-nonenal forms propano adducts with 2'-deoxyguanosine. It can also up-regulate cyclooxygenase-2 expression. As cyclooxygenase-2 converts linoleic acid into lipid hydroperoxides, this provides a potential mechanism for increased production of genotoxic bifunctional electrophiles. Malondialdehyde (beta-hydroxy-acrolein), another genotoxic bifunctional electrophile, is formed during homolytic decomposition of lipid hydroperoxides that contain more than two double bonds. Other sources of malondialdehyde include, hydroxyl radical-mediated decomposition of the 2'-deoxyribose DNA backbone and formation as a side-product during the biosynthesis of thromboxane A(2). Malondialdehyde reacts with DNA to form primarily a propano adduct with 2'-deoxyguanosine (M(1)G-dR). Significant advances in the characterization and analysis of lipid hydroperoxide-derived endogenous DNA-adducts have been made over the last decade so that dosimetry studies of human populations are now possible. Such studies will help elucidate the role of lipid hydroperoxide-derived endogenous DNA as mediators of cancer,
脂质氢过氧化物在体内通过活性氧对多不饱和脂肪酸的作用经自由基途径形成。它们也作为脂氧合酶和环氧化酶的特定产物而形成。脂质氢过氧化物向α,β-不饱和醛类基因毒素、4-氧代-2-壬烯醛、4,5-环氧-2(E)-癸烯醛和4-羟基-2-壬烯醛的均裂分解通过两条截然不同的途径发生。一条途径涉及源自脂质氢过氧化物的烷氧基自由基的复杂重排，另一条途径涉及另一种潜在基因毒素4-氢过氧-2-壬烯醛的中间形成。4,5-环氧-2(E)-癸烯醛与DNA形成未取代的乙烯基-2-脱氧腺苷加合物，这是一种在人体组织DNA样本中已观察到的诱变损伤。从4-氧代-2-壬烯醛与DNA的反应中已鉴定出几种新的乙醇基和乙烯基-DNA-加合物。4-羟基-2-壬烯醛与2'-脱氧鸟苷形成丙烷加合物。它还可上调环氧化酶-2的表达。由于环氧化酶-2将亚油酸转化为脂质氢过氧化物，这为遗传毒性双功能亲电试剂产量增加提供了一种潜在机制。丙二醛（β-羟基丙烯醛），另一种遗传毒性双功能亲电试剂，在含有两个以上双键的脂质氢过氧化物的均裂分解过程中形成。丙二醛的其他来源包括，羟基自由基介导的2'-脱氧核糖DNA主链的分解以及血栓素A(2)生物合成过程中作为副产物的形成。丙二醛与DNA反应主要形成与2'-脱氧鸟苷的丙烷加合物（M(1)G-dR）。在过去十年中，脂质氢过氧化物衍生的内源性DNA加合物的表征和分析取得了重大进展，因此现在对人群进行剂量学研究成为可能。此类研究将有助于阐明脂质氢过氧化物衍生的内源性DNA作为癌症介质的作用。
