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The role of one-electron reduction of lipid hydroperoxides in causing DNA damage.

ABSTRACT: The in vivo metabolism of plasma lipids generates lipid hydroperoxides that, upon one-electron reduction, give rise to a wide spectrum of genotoxic unsaturated aldehydes and epoxides. These metabolites react with cellular DNA to form a variety of pre-mutagenic DNA lesions. The mechanisms of action of the radical precursors of these genotoxic electrophiles are poorly understood. In this work we investigated the nature of DNA products formed by a one-electron reduction of (13S)-hydroperoxy-(9Z,11E)-octadecadienoic acid (13S-HPODE), a typical lipid molecule, and the reactions of the free radicals thus generated with neutral guanine radicals, G(-H)(*). A novel approach was devised to generate these intermediates in solution. The two-photon-induced ionization of 2-aminopurine (2AP) within the 2'-deoxyoligonucleotide 5'-d(CC[2AP]TCGCTACC) by intense nanosecond 308 nm excimer laser pulses was employed to simultaneously generate hydrated electrons and radical cations 2AP(*+). The latter radicals either in cationic or neutral forms, rapidly oxidize the nearby G base to form G(-H)(*). In deoxygenated buffer solutions (pH 7.5), the hydrated electrons rapidly reduce 13S-HPODE and the highly unstable alkoxyl radicals formed undergo a prompt beta-scission to pentyl radicals that readily combine with G(-H)(*). Two novel guanine products in these oligonucleotides, 8-pentyl- and N(2)-pentylguanine, were identified. It is shown that the DNA secondary structure significantly affects the ratio of 8-pentyl- and N(2)-pentylguanine lesions that changes from 0.9:1 in single-stranded, to 1:0.2 in double-stranded oligonucleotides. The alkylation of guanine by alkyl radicals derived from lipid hydroperoxides might contribute to the genotoxic modification of cellular DNA under hypoxic conditions. Thus, further research is warranted on the detection of pentylguanine lesions and other alkylguanines in vivo.

SUBMITTER: Crean C

PROVIDER: S-EPMC4036807 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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The role of one-electron reduction of lipid hydroperoxides in causing DNA damage.

Crean Conor C Shao Jie J Yun Byeong Hwa BH Geacintov Nicholas E NE Shafirovich Vladimir V

Chemistry (Weinheim an der Bergstrasse, Germany) 20091001 40

The in vivo metabolism of plasma lipids generates lipid hydroperoxides that, upon one-electron reduction, give rise to a wide spectrum of genotoxic unsaturated aldehydes and epoxides. These metabolites react with cellular DNA to form a variety of pre-mutagenic DNA lesions. The mechanisms of action of the radical precursors of these genotoxic electrophiles are poorly understood. In this work we investigated the nature of DNA products formed by a one-electron reduction of (13S)-hydroperoxy-(9Z,11E ...[more]

PMID: 19746460

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Project description:The Cu(II)-promoted oxidation of lipids is a lipid hydroperoxide (LOOH)-dependent process that has been used routinely to assess the oxidizability of low-density lipoprotein (LDL) in human subjects. Metal-dependent redox reactions, including those mediated by copper, have been implicated in the pathogenesis ofatherosclerosis. Despite its widespread use and possible biological significance, key elements of the mechanism are not clear. For example, although it is evident that copper acts as a catalyst, which implies a redox cycle between the Cu(II) and Cu(I) redox states, the reductants remain uncertain. In LDL these could include alpha-tocopherol, amino acid residues on the protein and LOOH. However, both alpha-tocopherol and amino acid residues are probably consumed before the most rapid phase of lipid peroxidation occurs, suggesting that another reductant must be donating electrons to Cu(II), the most likely candidate being LOOH. This role has been disputed, since LDLs nominally devoid of LOOH are still capable of reducing Cu(II) to Cu(I) and thermodynamic calculations for this reaction are not favourable. Direct investigation of the role of LOOH as reductant has not been reported and in the present study, using simple lipid systems and LDL, we have re-examined this issue using the Cu(I) chelator bathocuproine. We have shown that Cu(II) may promote lipid peroxidation in liposomes, which do not contain either protein or alpha-tocopherol, and that this is associated with reduction to Cu(I). The data also indicate that an equilibrium between free Cu(II) and LOOH exists, which only in the presence of an oxidizable substrate, i.e. unsaturated fatty acids, is shifted towards formation of Cu(I) and lipid-derived peroxyl radicals. We propose that reduction of Cu(II) by LOOH is a necessary component in sustaining the propagation of lipid peroxidation and that the formation of peroxyl radicals and their products in a lipid environment is sufficient to overcome thermodynamic barriers to the reaction.

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The role of one-electron reduction of lipid hydroperoxides in causing DNA damage.

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The role of one-electron reduction of lipid hydroperoxides in causing DNA damage.

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