反式-4-羟基壬烯醛的立体化学确定的1,N2-脱氧鸟苷加合物在哺乳动物细胞中的位点特异性诱变性。

Site-specific mutagenicity of stereochemically defined 1,N2-deoxyguanosine adducts of trans-4-hydroxynonenal in mammalian cells.

作者信息

Fernandes Priscilla H, Wang Hao, Rizzo Carmelo J, Lloyd R Stephen

机构信息

Sealy Center for Molecular Science and Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, Texas 77555, USA.

出版信息

Environ Mol Mutagen. 2003;42(2):68-74. doi: 10.1002/em.10174.

DOI:10.1002/em.10174

PMID:12929118

Abstract

Trans-4-hydroxynonenal (HNE) is a toxic compound produced endogenously during lipid peroxidation. HNE is a potent electrophile that is reactive with both proteins and nucleic acids. HNE preferentially reacts with deoxyguanosine to form four stereoisomeric HNE-deoxyguanosine (HNE-dG) adducts: (6R, 8S, 11R), (6S, 8R, 11S), (6R, 8S, 11S), and (6S, 8R, 11R). These adducts were synthesized into 12-mer oligodeoxynucleotides, inserted into a DNA shuttle vector and evaluated for the ability of each stereoisomer to induce mutagenesis when replicated through mammalian cells. The resultant mutagenicity of these adducts was related to their stereochemistry, in that two of the HNE-dG adducts, (6R, 8S, 11R) and (6S, 8R, 11S), were significantly more mutagenic than the (6R, 8S, 11S) and (6S, 8R, 11R) HNE-dG adducts. These data conclusively demonstrate that HNE-derived DNA adducts can be mutagenic in mammalian cells and their ability to cause mutations is dictated by their stereochemistry.

摘要

反式-4-羟基壬烯醛（HNE）是脂质过氧化过程中内源性产生的一种有毒化合物。HNE是一种强亲电试剂，能与蛋白质和核酸发生反应。HNE优先与脱氧鸟苷反应，形成四种立体异构的HNE-脱氧鸟苷（HNE-dG）加合物：（6R，8S，11R）、（6S，8R，11S）、（6R，8S，11S）和（6S，8R，11R）。将这些加合物合成到12聚体寡脱氧核苷酸中，插入到DNA穿梭载体中，并评估每种立体异构体在通过哺乳动物细胞复制时诱导诱变的能力。这些加合物产生的诱变性与其立体化学有关，其中两种HNE-dG加合物（6R，8S，11R）和（6S，8R，11S）的诱变性明显高于（6R，8S，11S）和（6S，8R，11R）HNE-dG加合物。这些数据确凿地证明，源自HNE的DNA加合物在哺乳动物细胞中具有诱变性，并且它们引起突变的能力由其立体化学决定。