DNA OXIDATION PRODUCTS AND ENDOGENOUS DNA ADDUCTS

描述（改编自申请人的摘要）：这是一份申请， 研究“内源性”DNA加合物的起源（即，那些没有衍生的 直接来自外源化学物质）。有待检验的假设是， 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。该假设基于申请人的观察，即 脱氧核糖的4 '-氧化产物与DNA反应形成诱变剂 鸟嘌呤加合物，以前认为是从丙二醛衍生而来， 脂质过氧化作用。本拟议项目将系统地探讨 通过几种亲电脱氧核糖氧化的DNA碱基加合化学 产品.目标1中的研究将检查基丙烯作为 鸟嘌呤嘧啶嘌呤酮，M1 G。将在暴露的DNA中测量M1 G加合物 在体外对DNA定向的氧化剂抗生素或过氧亚硝酸盐和铁-或 铜-过氧化氢混合物。在其他研究中， 脂质过氧化醛类产品和基础丙烯醛将比较， 酵母、细菌和哺乳动物细胞的氧化。目标2的研究将 研究磷酸甘油醛残基在乙烯基形成中的作用 DNA中腺嘌呤、鸟嘌呤和胞苷的加合物。与目标1相同，均在体外 DNA研究和细胞模型系统研究将用于比较 磷酸甘醛和脂质过氧化衍生的醛作为 乙烯加成物。目标3中的研究将通过以下方法检查碱基修饰的产物： 1，4-二氧代-2-丁烯和甲酰磷酸从5 '-H提取引发 脱氧核糖氧化aim 4的重点是 用于脱氧核糖研究的含[U-13 C]-和[U-14 C]-脱氧核糖的DNA 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.