Skip to main content
SpringerLink
Log in

Lipid Peroxide–DNA Adducts

  • Chapter
  • First Online:
Chemical Carcinogenesis

Part of the book series: Current Cancer Research ((CUCR))

Abstract

Increased production of reactive oxygen species during oxidative stress can initiate the formation of lipid hydroperoxides, which undergo homolytic decomposition to the α, β-unsaturated aldehydic bifunctional electrophiles, 4-oxo-2(E)-nonenal (ONE), 4-hydroxy-2(E)-nonenal (HNE), 4-hydroperoxy-2(E)-nonenal (HPNE), and malondialdehyde (MDA). Excessive lipid hydroperoxides can also be derived from the up-regulation of lipoxygenases (LOXs) and cyclooxygenases (COXs). Intracellular generation of the bifunctional electrophiles can then result in the formation of glutathione (GSH), protein, and DNA adducts. The analysis of lipid hydroperoxide-derived DNA adducts, such as ONE-derived heptanone-etheno DNA (HεDNA) adducts, can facilitate molecular epidemiology studies by providing insight into the amount of a genotoxin that has reached the DNA of the tissue under study. In addition, HεDNA adducts that are repaired and excreted in the urine can be used as specific biomarkers of lipid peroxidation-mediated DNA damage.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 179.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 229.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Ames BN, Shigenaga MK, Hagen TM (1993) Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci USA 90:7915–7922

    Article  PubMed  CAS  Google Scholar 

  • Bartsch H, Nair J (2006) Chronic inflammation and oxidative stress in the genesis and perpetuation of cancer: role of lipid peroxidation, DNA damage, and repair. Langenbecks Arch Surg 5:499–510

    Article  PubMed  CAS  Google Scholar 

  • Blair IA (2006) Endogenous glutathione adducts. Curr Drug Metab 7:853–872

    Article  PubMed  CAS  Google Scholar 

  • Blair IA (2008) DNA adducts with lipid peroxidation products. J Biol Chem 283:15545–15549

    Article  PubMed  CAS  Google Scholar 

  • Blair IA (2010) Analysis of endogenous glutathione-adducts and their metabolites. Biomed Chromatogr 24:29–38

    Article  PubMed  CAS  Google Scholar 

  • Blair IA (2010) Analysis of estrogens in serum and plasma from postmenopausal women: past, present, and future. Steroids 75:297–306. DOI:10.1016/j.steroids.2010.01.012

    Article  PubMed  CAS  Google Scholar 

  • Burcham PC (1998) Genotoxic lipid peroxidation products: their DNA damaging properties and role in formation of endogenous DNA adducts. Mutagenesis 13:287–305

    Article  PubMed  CAS  Google Scholar 

  • Chaudhary A, Nokubo M, Reddy GR, Yeola SN, Morrow JD, Blair IA, Marnett LJ (1994a) Detection of endogenous malondialdehyde-deoxyguanosine adducts in human liver. Science 265:1580–1582

    Article  PubMed  CAS  Google Scholar 

  • Chaudhary AK, Nokubo M, Marnett LJ, Blair IA (1994b) Analysis of the malondialdehyde-2′-deoxyguanosine adduct in rat liver DNA by gas chromatography/electron capture negative chemical ionization mass spectrometry. Biol Mass Spectrom 23:457–464

    Article  PubMed  CAS  Google Scholar 

  • Chen HJ, Chiang LC, Tseng MC, Zhang LL, Ni J, Chung FL (1999) Detection and quantification of 1,N  6-ethenoadenine in human placental DNA by mass spectrometry. Chem Res Toxicol 12:1119–1126

    Article  PubMed  CAS  Google Scholar 

  • Chernyak BV (1997) Redox regulation of the mitochondrial permeability transition pore. Biosci Rep 17:293–302

    Article  PubMed  CAS  Google Scholar 

  • Churg A (2003) Interactions of exogenous or evoked agents and particles: the role of reactive oxygen species. Free Radic Biol Med 34:1230–1235

    Article  PubMed  CAS  Google Scholar 

  • Ciccimaro E, Blair IA (2010) Stable-isotope dilution LC–MS for quantitative biomarker analysis. Bioanalysis 2:311–341

    Article  PubMed  CAS  Google Scholar 

  • Cook JA, Gius D, Wink DA, Krishna MC, Russo A, Mitchell JB (2004) Oxidative stress, redox, and the tumor microenvironment. Semin Radiat Oncol 14:259–266

    Article  PubMed  Google Scholar 

  • Dickinson DA, Forman HJ (2002) Cellular glutathione and thiols metabolism. Biochem Pharmacol 64:1019–1026

    Article  PubMed  CAS  Google Scholar 

  • Doerge DR, Churchwell MI, Fang JL, Beland FA (2000) Quantification of etheno-DNA adducts using liquid chromatography, on-line sample processing, and electrospray tandem mass spectrometry. Chem Res Toxicol 13:1259–1264

    Article  PubMed  CAS  Google Scholar 

  • Douki T, Odin F, Caillat S, Favier A, Cadet J (2004) Predominance of the 1,N   2-propano 2′-deoxyguanosine adduct among 4-hydroxy-2-nonenal-induced DNA lesions. Free Radic Biol Med 37:62–70

    Article  PubMed  CAS  Google Scholar 

  • Evans DC, Watt AP, Nicoll-Griffith DA, Baillie TA (2004) Drug-protein adducts: an industry perspective on minimizing the potential for drug bioactivation in drug discovery and development. Chem Res Toxicol 17:3–16

    Article  PubMed  CAS  Google Scholar 

  • Funk CD (2001) Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 294:1871–1875

    Article  PubMed  CAS  Google Scholar 

  • Gonzalez FJ (2005) Role of cytochromes P450 in chemical toxicity and oxidative stress: studies with CYP2E1. Mutat Res 569:101–110

    PubMed  CAS  Google Scholar 

  • Homolya L, Váradi A, Sarkadi B (2003) Multidrug resistance-associated proteins: export pumps for conjugates with glutathione, glucuronate or sulfate. Biofactors 17:103–114

    Article  PubMed  CAS  Google Scholar 

  • Jian W, Lee SH, Arora JS, Silva Elipe MV, Blair IA (2005a) Unexpected formation of etheno-2′-deoxyguanosine adducts from 5(S)-hydroperoxyeicosatetraenoic acid: evidence for a bis-hydroperoxide intermediate. Chem Res Toxicol 18:599–610

    Article  PubMed  CAS  Google Scholar 

  • Jian W, Arora JS, Oe T, Shuvaev VV, Blair IA (2005b) Induction of endothelial cell apoptosis by lipid hydroperoxide-derived bifunctional electrophiles. Free Radic Biol Med 39:1162–1176

    Article  PubMed  CAS  Google Scholar 

  • Jian W, Lee SH, Williams MV, Blair IA (2009) 5-Lipoxygenase-mediated endogenous DNA damage. J Biol Chem 284:16799–16807

    Article  PubMed  CAS  Google Scholar 

  • Kühn H, Borchert A (2002) Regulation of enzymatic lipid peroxidation: the interplay of peroxidizing and peroxide reducing enzymes. Free Radic Biol Med 33:154–172

    Article  PubMed  Google Scholar 

  • Kühn H, O’Donnell VB (2006) Inflammation and immune regulation by 12/15-lipoxygenases. Prog Lipid Res 45:334–356

    Article  PubMed  Google Scholar 

  • Lee SH, Blair IA (2001) Oxidative DNA damage and cardiovascular disease. Trends Cardiovasc Med 11:148–155

    Article  PubMed  CAS  Google Scholar 

  • Lee SH, Blair IA (2007) Targeted chiral lipidomics analysis by liquid chromatography electron capture atmospheric pressure chemical ionization mass spectrometry (LC–ECAPCI/MS). Methods Enzymol 433:159–174

    Article  PubMed  CAS  Google Scholar 

  • Lee SH, Blair IA (2009) Targeted chiral lipidomics analysis of bioactive eicosanoid lipids in cellular systems. BMB Rep 42:401–410

    PubMed  CAS  Google Scholar 

  • Lee SH, Rindgen D, Bible RH Jr, Hajdu E, Blair IA (2000) Characterization of 2′-deoxyadenosine adducts derived from 4-oxo-2-nonenal, a novel product of lipid peroxidation. Chem Res Toxicol 13:565–574

    Article  PubMed  CAS  Google Scholar 

  • Lee SH, Oe T, Blair IA (2001) Vitamin C-induced decomposition of lipid hydroperoxides to endogenous genotoxins. Science 292:2083–2086

    Article  PubMed  CAS  Google Scholar 

  • Lee SH, Oe T, Blair IA (2002) 4,5-Epoxy-2(E)-decenal-induced formation of 1,N  6-etheno-2′-deoxyadenosine and 1,N   2-etheno-2′-deoxyguanosine adducts. Chem Res Toxicol 15:300–304

    Article  PubMed  CAS  Google Scholar 

  • Lee SH, Williams MV, Dubois RN, Blair IA (2003) Targeted lipidomics using electron capture atmospheric pressure chemical ionization mass spectrometry. Rapid Commun Mass Spectrom 17:2168–2176.

    Article  PubMed  CAS  Google Scholar 

  • Lee SH, Williams MV, DuBois RN, Blair IA (2005a) Cyclooxygenase-2-mediated DNA damage. J Biol Chem 280:28337–28346

    Article  PubMed  CAS  Google Scholar 

  • Lee SH, Oe T, Arora JS, Blair IA (2005b) Analysis of FeII-mediated decomposition of a linoleic acid-derived lipid hydroperoxide by liquid chromatography/mass spectrometry. J Mass Spectrom 40:661–668

    Article  PubMed  CAS  Google Scholar 

  • Lee SH, Arora JA, Oe T, Blair IA (2005c) 4-Hydroperoxy-2-nonenal-induced formation of 1,N 2-etheno-2′-deoxyguanosine adducts. Chem Res Toxicol 18:780–786

    Article  PubMed  CAS  Google Scholar 

  • Lee SH, Silva Elipe MV, Arora JS, Blair IA (2005d) Dioxododecenoic acid: a lipid hydroperoxide-derived bifunctional electrophile responsible for etheno DNA adduct formation. Chem Res Toxicol 18:566–578

    Article  PubMed  CAS  Google Scholar 

  • Lee SH, Rangiah K, Williams MV, Wehr AY, DuBois RN, Blair IA (2007) Cyclooxygenase-2-mediated metabolism of arachidonic acid to 15-oxo-eicosatetraenoic acid by rat intestinal epithelial cells. Chem Res Toxicol 20:1665–1675

    Article  PubMed  CAS  Google Scholar 

  • Lee SH, Goto T, Oe T (2008) A novel 4-oxo-2(E)-nonenal-derived modification to angiotensin II: oxidative decarboxylation of N-terminal aspartic acid. Chem Res Toxicol 21:2237–2244

    Article  PubMed  CAS  Google Scholar 

  • Loureiro AP, Di MP, Gomes OF, Medeiros MH (2000) trans,trans-2,4-Decadienal-induced 1,N 2-etheno-2′-deoxyguanosine adduct formation. Chem Res Toxicol 13:601–609

    Article  PubMed  CAS  Google Scholar 

  • Manevich Y, Fisher AB (2005) Peroxiredoxin 6, a 1-Cys peroxiredoxin, functions in antioxidant defense and lung phospholipid metabolism. Free Radic Biol Med 38:1422–1432

    Article  PubMed  CAS  Google Scholar 

  • Marnett LJ (1999) Lipid peroxidation-DNA damage by malondialdehyde. Mutat Res 424:83–95

    PubMed  CAS  Google Scholar 

  • Marnett LJ (2000) Oxyradicals and DNA damage. Carcinogenesis 21:361–370

    Article  PubMed  CAS  Google Scholar 

  • Mesaros C, Lee SH, Blair IA (2009) Targeted quantitative analysis of eicosanoid lipids in biological samples using liquid chromatography–tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 877:2736–2745

    Article  PubMed  CAS  Google Scholar 

  • Minko IG, Kozekov ID, Harris TM, Rizzo CJ, Lloyd RS, Stone MP (2009) Chemistry and biology of DNA containing 1,N2-deoxyguanosine adducts of the a, b-unsaturated aldehydes acrolein, crotonaldehyde, and 4-hydroxynonenal. Chem Res Toxicol 22:759–778

    Article  PubMed  CAS  Google Scholar 

  • Nath RG, Ocando JE, Guttenplan JB, Chung FL (1998) 1,N 2-Propanodeoxyguanosine adducts: potential new biomarkers of smoking-induced DNA damage in human oral tissue. Cancer Res 58:581–584

    PubMed  CAS  Google Scholar 

  • Oe T, Arora JS, Lee SH, Blair IA (2003) A novel lipid hydroperoxide-derived cyclic covalent modification to histone H4. J Biol Chem 278:42098–42105

    Article  PubMed  CAS  Google Scholar 

  • Pollack M, Oe T, Lee SH, Silva Elipe MV, Arison BH, Blair IA (2003) Characterization of 2′-deoxycytidine adducts derived from 4-oxo-2-nonenal, a novel lipid peroxidation product. Chem Res Toxicol 16:893–900

    Article  PubMed  CAS  Google Scholar 

  • Pollack M, Yang IY, Kim HY, Blair IA, Moriya M (2006) Translesion DNA synthesis across the heptanone–etheno-2′-deoxycytidine adduct in cells. Chem Res Toxicol 19:1074–1079

    Article  PubMed  CAS  Google Scholar 

  • Porter NA, Caldwell SE, Mills KA (1995) Mechanisms of free radical oxidation of unsaturated lipids. Lipids 30:277–290

    Article  PubMed  CAS  Google Scholar 

  • Rindgen D, Nakajima M, Wehrli S, Xu K, Blair IA (1999) Covalent modification of 2′-deoxyguanosine by products of lipid peroxidation. Chem Res Toxicol 12:1195–1204

    Article  PubMed  CAS  Google Scholar 

  • Rindgen D, Lee SH, Nakajima M, Blair IA (2000) Formation of a substituted 1,N 6-etheno-2′-deoxyadenosine adduct by lipid hydroperoxide-mediated generation of 4-oxo-2-nonenal. Chem Res Toxicol 13:846–852

    Article  PubMed  CAS  Google Scholar 

  • Robbins DH, Itzkowitz SH (2002) The molecular and genetic basis of colon cancer. Med Clin North Am 86:1467–1495

    Article  PubMed  CAS  Google Scholar 

  • Rouzer CA, Marnett LJ (2008) Non-redundant functions of cyclooxygenases: oxygenation of endocannabinoids. J Biol Chem 283:8065–8069

    Article  PubMed  CAS  Google Scholar 

  • Rouzer CA, Chaudhary AK, Nokubo M, Ferguson DM, Reddy GR, Blair IA, Marnett LJ (1997) Analysis of the malondialdehyde-2′-deoxyguanosine adduct pyrimidopurinone in human leukocyte DNA by gas chromatography/electron capture/negative chemical ionization/mass spectrometry. Chem Res Toxicol 10:181–188

    Article  PubMed  CAS  Google Scholar 

  • Sayre LM, Lin D, Yuan Q, Zhu X, Tang X (2006) Protein adducts generated from products of lipid oxidation: focus on HNE and ONE. Drug Metab Rev 38:651–675.

    Article  PubMed  CAS  Google Scholar 

  • Schneider C, Tallman KA, Porter NA, Brash AR (2001) Two distinct pathways of formation of 4-hydroxynonenal: mechanisms of nonenzymatic transformation of the 9- and 13-hydroperoxides of linoleic acid to 4-hydroxyalkenals. J Biol Chem 276:20831–20838

    Article  PubMed  CAS  Google Scholar 

  • Schneider C, Boeglin WE, Yin H, Ste DF, Hachey DL, Porter NA, Brash AR (2005) Synthesis of dihydroperoxides of linoleic and linolenic acids and studies on their transformation to 4-hydroperoxynonenal. Lipids 40:1155–1162

    Article  PubMed  CAS  Google Scholar 

  • Schneider C, Pratt DA, Porter NA, Brash AR (2007) Control of oxygenation in lipoxygenase and cyclooxygenase catalysis. Chem Biol 14:473–488

    Article  PubMed  CAS  Google Scholar 

  • Schneider C, Porter NA, Brash AR (2008) Routes to 4-hydroxynonenal: fundamental issues in the mechanisms of lipid peroxidation. J Biol Chem 283:15539–15543

    Article  PubMed  CAS  Google Scholar 

  • Schneider C, Boeglin WE, Yin H, Porter NA, Brash AR (2008) Intermolecular peroxyl radical reactions during autoxidation of hydroxy and hydroperoxy arachidonic acids generate a novel series of epoxidized products. Chem Res Toxicol 21:895–903

    Article  PubMed  CAS  Google Scholar 

  • Singh G, Gutierrez A, Xu K, Blair IA (2000) Liquid chromatography/electron capture atmospheric pressure chemical ionization/mass spectrometry: analysis of pentafluorobenzyl derivatives of biomolecules and drugs in the attomole range. Anal Chem 72:3007–3013

    Article  PubMed  CAS  Google Scholar 

  • Sodum RS, Chung FL (1991) Stereoselective formation of in vitro nucleic acid adducts by 2,3-epoxy-4-hydroxynonanal. Cancer Res 51:137–143

    PubMed  CAS  Google Scholar 

  • Swenberg JA, Fedtke N, Ciroussel F, Barbin A, Bartsch H (1992) Etheno adducts formed in DNA of vinyl chloride-exposed rats are highly persistent in liver. Carcinogenesis 13:727–729

    Article  PubMed  CAS  Google Scholar 

  • Swenberg JA, Bogdanffy MS, Ham A, Holt S, Kim A, Morinello EJ, Ranasinghe A, Scheller N, Upton PB (1999) Exocyclic DNA adducts. In: Singer B, Bartsch H (eds) Mutagenesis and carcinogenesis, vol 150. IARC Science Publications, Lyon, France, pp 29–43

    Google Scholar 

  • Uchida K (2003) 4-Hydroxy-2-nonenal: a product and mediator of oxidative stress. Prog Lipid Res 42:318–343

    Article  PubMed  CAS  Google Scholar 

  • Watson WP, Mutti A (2004) Role of biomarkers in monitoring exposures to chemicals: present position, future prospects. Biomarkers 9:211–242

    Article  PubMed  CAS  Google Scholar 

  • Williams MV, Lee SH, Blair IA (2005) Liquid chromatography/mass spectrometry analysis of bifunctional electrophiles and DNA adducts from vitamin C mediated decomposition of 15-hydroperoxyeicosatetraenoic acid. Rapid Commun Mass Spectrom 19:849–858

    Article  PubMed  CAS  Google Scholar 

  • Williams MV, Lee SH, Pollack M, Blair IA (2006) Endogenous lipid hydroperoxide-mediated DNA-adduct formation in Min mice. J Biol Chem 281:10127–10133

    Article  PubMed  CAS  Google Scholar 

  • Yang IY, Hashimoto K, de Wind N, Blair IA, Moriya M (2009) Two distinct translesion synthesis pathways across a lipid peroxidation-derived DNA adduct in mammalian cells. J Biol Chem 284:191–198

    Article  PubMed  CAS  Google Scholar 

  • Yi P, Zhan DJ, Samokyszyn VM, Doerge DR, Fu PP (1997) Synthesis and 32P-postlabeling/high performance liquid chromatography separation of diastereomeric 1,N   2-(1,3-propano)-2′-deoxyguanosine 3′-phosphate adducts formed from 4-hydroxy-2-nonenal. Chem Res Toxicol 10:1259–1265

    Article  PubMed  CAS  Google Scholar 

  • Zhou X, Taghizadeh K, Dedon PC (2005) Chemical and biological evidence for base propenals as the major source of the endogenous M1dG adduct in cellular DNA. J Biol Chem 280:25377–25382

    Article  PubMed  CAS  Google Scholar 

  • Zhu P, Lee SH, Wehrli S, Blair IA (2006) Characterization of a lipid hydroperoxide-derived RNA adduct in rat intestinal epithelial cells. Chem Res Toxicol 19:809–817

    Article  PubMed  CAS  Google Scholar 

  • Zhu P, Oe T, Blair IA (2008) Determination of cellular redox status by stable isotope dilution liquid chromatography/mass spectrometry analysis of glutathione and glutathione disulfide. Rapid Commun Mass Spectrom 22:432–440

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We acknowledge the support of NIH grants RO1CA091016 and P30ES013508.

Author information

Authors and Affiliations

  1. Department of Pharmacology, Center for Cancer Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Ian A. Blair

  2. Department of Pharmacology, Center of Excellence in Environmental Toxicology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Ian A. Blair

Authors
  1. Seon Hwa Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ian A. Blair
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ian A. Blair .

Editor information

Editors and Affiliations

  1. School of Medicine, Dept. Pharmacology, University of Pennsylvania, Hamilton Walk 3260, Philadelphia, 19104, Pennsylvania, USA

    Trevor M. Penning

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Lee, S.H., Blair, I.A. (2011). Lipid Peroxide–DNA Adducts. In: Penning, T. (eds) Chemical Carcinogenesis. Current Cancer Research. Humana Press. https://doi.org/10.1007/978-1-61737-995-6_11

Download citation

  • DOI: https://doi.org/10.1007/978-1-61737-995-6_11

  • Published:

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-61737-994-9

  • Online ISBN: 978-1-61737-995-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation