Comparative evaluation of the bioreactivity and mutagenic spectra of acrolein-derived α-HOPdG and γ-HOPdG regioisomeric deoxyguanosine adducts
Comparative evaluation of the bioreactivity and mutagenic spectra of acrolein-derived α-HOPdG and γ-HOPdG regioisomeric deoxyguanosine adducts
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DOI：
10.1021/tx034066u
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发表时间：
2003-08-01
影响因子：
4.1
通讯作者：
Lloyd, RS
中科院分区：
文献类型：
--
作者：
Sanchez, AM;Minko, IG;Lloyd, RS
丙烯醛是一种双功能亲电体，作为一种普遍存在的环境污染物和脂质过氧化的内源性细胞产物存在。丙烯醛与脱氧鸟苷的反应产生两种区域异构的DNA加合物，特别是γ-羟基丙脱氧鸟苷（γ-HOPdG）和α-羟基丙脱氧鸟苷（α-HOPdG）。虽然以前的研究集中在主要的γ-HOPdG加合物，很少有人知道的次要（α-HOPdG加合物的性质。因此，本比较研究评估了以下内容：在哺乳动物细胞中复制后，每种加合物与生物分子发生二次化学反应以形成各种交联物质的能力、体外translesion DNA合成和致突变特性。与能够形成DNA-DNA、DNA-肽和DNA-蛋白质交联的γ-HOPdG相反，α-HOPdG不形成任何这些交联物质。这些结果可以归因于α-HOPdG加合物不能进行开环，而γ-HOPdG加合物在双链体DNA中形成开环的无环N-2氧代丙基，其容易与亲核官能团反应。与这种解释一致，当测定含有α-HOPdG的DNA的聚合酶eta复制旁路时，这种损伤比γ-HOPdG加合物对复制造成更强的阻断，非常类似于环外加合物保持永久闭环的丙脱氧鸟苷的聚合酶eta旁路的结果。使用含有位点特异性α-HOPdG的单链DNA在COS-7细胞中进行的细胞复制和诱变试验表明，该加合物具有显著的诱变性，与γ-HOPdG加合物相比，产生几乎相同的突变频率和谱。
Acrolein is a bifunctional electrophile, present as an ubiquitous environmental pollutant and an endogenous cellular product of lipid peroxidation. Reaction of acrolein with deoxyguanosine produces two regioisomeric DNA adducts, specifically gamma-hydroxypropanodeoxyguanosine (gamma-HOPdG) and alpha-hydroxypropanodeoxyguanosine ((alpha-HOPdG). While previous investigations have focused on the major gamma-HOPdG adduct, little is known about the properties of the minor (alpha-HOPdG adduct. Therefore, this comparative investigation has assessed the following: the ability of each adduct to undergo secondary chemical reactions with biomolecules to form various cross-linked species, in vitro translesion DNA synthesis, and mutagenic properties, following replication in mammalian cells. In contrast to gamma-HOPdG, which is capable of forming DNA-DNA, DNA-peptide, and DNA-protein cross-links, (alpha-HOPdG did not form any of these cross-linked species. These results can be attributed to the inability of the alpha-HOPdG adduct to undergo ring opening, whereas the gamma-HOPdG adduct forms the ring open, acyclic N-2 oxopropyl in duplex DNA, which readily reacts with nucleophilic functions. Consistent with this interpretation, when polymerase eta replication bypass of DNA containing alpha-HOPdG was assayed, this lesion posed a stronger block to replication than the y-HOPdG adduct, closely resembling the results for polymerase eta bypass of propanodeoxyguanosine in which the exocyclic adduct remains permanently ring-closed. Cellular replication and mutagenesis assays in COS-7 cells using single-stranded DNA containing a site specific alpha-HOPdG revealed that this adduct was significantly mutagenic, yielding a nearly identical frequency and spectrum of mutations as compared with the gamma-HOPdG adduct.