Endogenous formation and significance of 1,N2-propanodeoxyguanosine adducts
Endogenous formation and significance of 1,N2-propanodeoxyguanosine adducts
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DOI：
10.1016/s0027-5107(99)00009-3
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发表时间：
1999-03-08
影响因子：
2.3
通讯作者：
Randerath, K
中科院分区：
文献类型：
--
作者：
Chung, FL;Nath, RG;Randerath, K
在啮齿类动物和人类组织的DNA中检测到1，N-2-丙脱氧鸟苷加合物作为内源性病变，提出了关于其形成来源及其在致癌作用中的作用的重要问题。体外和体内研究都产生了大量证据，支持氧化多不饱和脂肪酸（PUFA）衍生的短链和长链烯醛参与其形成。这些研究表明：（1）环丙烷加合物是烯醛与DNA碱基反应的常见产物;（2）它们是由亚油酸特异性形成的（3）在谷胱甘肽耗尽后，大鼠肝DNA中丙烷加合物的水平显著增加;（4）在经四氯化碳处理的大鼠和遗传上易引起脂质过氧化增加的Long Evans大鼠突变品系的肝脏DNA中，加合物水平增加;（5）老年大鼠的加合物水平明显高于新生大鼠。这些研究共同表明，组织脂质过氧化是导致DNA中丙烷加合的主要内源性途径。然而，不能完全排除环境来源的可能贡献。烯醛的致突变性和使用模型1，N-2-丙氧鸟苷加合物的位点特异性致突变研究中观察到的突变表明，这些加合物是潜在的致突变损伤。致癌物处理的动物组织中丙烷加合物水平的增加也为它们在致癌作用中的作用提供了暗示性证据。推测这些加合物参与肿瘤促进的基础上，认为组织中的氧化条件与此过程有关。(C)1999 Elsevier Science B. V.保留所有权利。
The detection of 1,N-2-propanodeoxyguanosine adducts in the DNA of rodent and human tissues as endogenous lesions has raised important questions regarding the source of their formation and their roles in carcinogenesis. Both in vitro and in vivo studies have generated substantial evidence which supports the involvement of short- and long-chain enals derived from oxidized polyunsaturated fatty acids (PUFAs) in their formation. These studies show that: (1) the cyclic propane adducts are common products from reactions of enals with DNA bases; (2) they are formed specifically from linoleic acid (LA; omega-6) and docosahexaenoic acid (omega-3) under in vitro stimulated lipid peroxidation conditions; (3) the levels of propane adducts are dramatically increased in rat liver DNA upon depletion of glutathione; (4) the adduct levels are increased in the liver DNA of the CCl4-treated rats and the mutant strain of Long Evans rats which are genetically predisposed to increased lipid peroxidation; and (5) adduct levels are significantly higher in older rats than in newborn rats. These studies collectively demonstrate that tissue Lipid peroxidation is a main endogenous pathway leading to propane adduction in DNA. The possible contribution from environmental sources, however, cannot be completely excluded. The mutagenicity of enals and the mutations observed in site-specific mutagenesis studies using a model 1,N-2-propanodeoxyguanosine adduct suggest that these adducts are potential promutagenic lesions. The increased levels of the propane adducts in the tissue of carcinogen-treated animals also provide suggestive evidence for their roles in carcinogenesis. The involvement of these adducts in tumor promotion is speculated on the basis that oxidative condition in tissues is believed to be associated with this process. (C) 1999 Elsevier Science B.V. All rights reserved.