Burcham P C
Department of Clinical and Experimental Pharmacology, The University of Adelaide, SA, Australia.
Mutagenesis. 1998 May;13(3):287-305. doi: 10.1093/mutage/13.3.287.
The peroxidation of polyunsaturated lipids generates a range of substances that possess DNA damaging potential. This includes lipid hydroperoxides and various species that contain unpaired electrons, such as the alkoxyl and peroxyl radicals. In addition, a range of genotoxic carbonyl-containing compounds are formed, such as malondialdehyde, various 4-hydroxy-2-alkenals such as 4-hydroxynonenal and a number of 2-alkenals. It has previously been assumed that the antioxidants and electrophile scavenging enzymes existing in mammalian cells effectively protect the genetic material against these substances. However, thanks to recent analytical advances in the detection of low levels of DNA adducts, it is now evident that DNA adducts formed from a range of lipid peroxidation products are abundant in both rodent and human genomes. This suggests that the cellular defence system is not 100% efficient and that a proportion of endogenously produced lipid peroxidation products escape detoxification and cause DNA damage. This review surveys the genotoxic properties of the major classes of lipid peroxidation products, focusing on their chemistry of DNA adduction, the mutagenic properties of such damage and the evidence that it occurs in intact biological systems. Furthermore, avenues of future research that will clarify the significance of such damage to spontaneous mutagenesis and carcinogenesis are proposed and discussed.
多不饱和脂质的过氧化作用会产生一系列具有潜在DNA损伤能力的物质。这包括脂质氢过氧化物以及各种含有未成对电子的物种，如烷氧基和过氧自由基。此外，还会形成一系列具有基因毒性的含羰基化合物，如丙二醛、各种4-羟基-2-烯醛（如4-羟基壬烯醛）和一些2-烯醛。此前人们一直认为，哺乳动物细胞中存在的抗氧化剂和亲电体清除酶能有效保护遗传物质免受这些物质的侵害。然而，由于最近在检测低水平DNA加合物方面的分析进展，现在很明显，由一系列脂质过氧化产物形成的DNA加合物在啮齿动物和人类基因组中都很丰富。这表明细胞防御系统并非100%有效，一部分内源性产生的脂质过氧化产物逃脱了解毒过程并导致DNA损伤。本综述调查了主要类别的脂质过氧化产物的基因毒性特性，重点关注它们与DNA加合的化学过程、此类损伤的诱变特性以及其在完整生物系统中发生的证据。此外，还提出并讨论了未来的研究方向，这些研究将阐明此类损伤对自发诱变和致癌作用的重要性。
