DNA OXIDATION PRODUCTS AND ENDOGENOUS DNA ADDUCTS

描述(改编自申请人的摘要)：这是一份申请 调查“内源性”DNA加合物(即那些不是衍生的)的来源 直接来自外源化学品)。需要检验的假设是 DNA中脱氧核糖氧化的亲电产物可以与碱基反应 形成加合物。这一假设是基于申请人的观察结果，即 脱氧核糖的4‘-氧化产物与DNA反应形成诱变剂 鸟嘌呤加成物以前被认为来自丙二醛，一种产物 是脂质过氧化的结果。这项拟议的项目将系统地探索 几种亲电脱氧核糖氧化作用下DNA碱基加合的化学 产品。目标1中的研究将检查碱性丙烯作为 鸟嘌呤中的嘧啶并嘌呤，M1G。M1G加合物将在暴露的DNA中进行测量 在体外对DNA导向的氧化性抗生素或过氧亚硝酸根和铁-或 铜-过氧化氢混合物。在其他研究中，相对的作用是 脂质过氧化产物和碱性丙烯将在 与酵母、细菌和哺乳动物细胞的氧化作用。AIM 2中的研究将 研究磷酸糖醛残基在亚乙基形成中的作用 DNA中腺嘌呤、鸟嘌呤和胞苷的加合物。和目标1一样，都是在体外 DNA研究和细胞模型系统研究将被用来比较 磷酸乙醛和脂质过氧化衍生的醛作为 亚乙基加合物。目标3中的研究将通过以下方式检查碱基修饰产品 从5‘-H中提取1，4-二氧代-2-丁烯和甲酰磷酸 DNA中的脱氧核糖氧化。目标4的重点是生物合成 [U-13C]-和[U-14C]-脱氧核糖DNA用于脱氧核糖的研究 加合物的起源。

DESCRIPTION (adapted from the applicant's abstract): This is an application to investigate the origin of "endogenous" DNA adducts (i.e., those not derived directly from exogenous chemicals). The hypothesis to be tested is that electrophilic products of deoxyribose oxidation in DNA can react with bases to form adducts. This hypothesis is based on the applicant's observation that a product of 4'-oxidation of deoxyribose reacts with DNA to form a mutagenic guanine adduct previously thought to be derived from malondialdehyde, a product of lipid peroxidation. This proposed project will systematically explore the chemistry of DNA base adduction by several electrophilic deoxyribose oxidation products. Studies in aim 1 will examine base propenals as a source of the pyrimidopurinone of guanine, M1G. M1G adducts will be measured in DNA exposed in vitro toDNA-directed oxidant antibiotics or to peroxynitrite and iron- or copper-hydrogen peroxide mixtures. In other studies, the relative roles of lipid peroxidation aldehyde products and base propenals will be compared in oxidations with yeast, bacteria and mammalian cells. Studies in aim 2 will examine the role of phosphoglycoaldehyde residues in the formation of etheno adducts of adenine, guanine and cytidine in DNA. As in aim 1, both in vitro studies with DNA and studies with cell model systems will be used to compare phosphoglycoaldehyde and lipid peroxidation-derived aldehydes as sources of etheno adducts. Studies in aim 3 will examine products of base modification by 1,4-dioxo-2-butene and formyl phosphate from 5'-H abstraction-initiated deoxyribose oxidation in DNA. The focus of aim 4 is the biosynthesis of [U-13C]- and [U-14C]-deoxyribose-containing DNA for studies of the deoxyribose origin of adducts.