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

Conor Crean, Jie Shao, Byeong Hwa Yun, Nicholas E. Geacintov, Vladimir Shafirovich

Research output: Contribution to journalArticle

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 premutagenic 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 (135)-hydroperoxy-(9Z,11E)-octadecadienoic acid (135-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 gen- erate 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 135-HPODE and the highly unstable alkoxyl radicals formed undergo a prompt β-scission to pentyl radicals that readily combine with G(-H): Two novel guanine products in these oligonucleotides, 8-pentyl- and N2-pentylguanine, were identified. It is shown that the DNA secondary structure significantly affects the ratio of 8pentyl- and N2- pentylguanine lesions that changes from 0.9:1 in singlestranded, 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.

Original languageEnglish (US)
Pages (from-to)10634-10640
Number of pages7
JournalChemistry - A European Journal
Volume15
Issue number40
DOIs
StatePublished - Oct 12 2009

Fingerprint

Lipid Peroxides
2-Aminopurine
DNA
Guanine
Electrons
Oligonucleotides
Lipids
Acids
Epoxy Compounds
Alkylation
Excimer lasers
Metabolites
Aldehydes
Free radicals
Metabolism
Free Radicals
Ionization
Cations
Laser pulses
Buffers

Keywords

  • Alkylation
  • DNA damage
  • Free radical
  • Lipid hydroperoxide
  • One-electron reduction

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

The role of one-electron reduction of lipid hydroperoxides in causing DNA damage. / Crean, Conor; Shao, Jie; Yun, Byeong Hwa; Geacintov, Nicholas E.; Shafirovich, Vladimir.

In: Chemistry - A European Journal, Vol. 15, No. 40, 12.10.2009, p. 10634-10640.

Research output: Contribution to journalArticle

Crean, Conor ; Shao, Jie ; Yun, Byeong Hwa ; Geacintov, Nicholas E. ; Shafirovich, Vladimir. / The role of one-electron reduction of lipid hydroperoxides in causing DNA damage. In: Chemistry - A European Journal. 2009 ; Vol. 15, No. 40. pp. 10634-10640.
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AB - 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 premutagenic 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 (135)-hydroperoxy-(9Z,11E)-octadecadienoic acid (135-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 gen- erate 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 135-HPODE and the highly unstable alkoxyl radicals formed undergo a prompt β-scission to pentyl radicals that readily combine with G(-H): Two novel guanine products in these oligonucleotides, 8-pentyl- and N2-pentylguanine, were identified. It is shown that the DNA secondary structure significantly affects the ratio of 8pentyl- and N2- pentylguanine lesions that changes from 0.9:1 in singlestranded, 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.

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