Home LiteratureArticle Details
PMID: 18500830 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Interstrand DNA cross-links induced by alpha,beta-unsaturated aldehydes derived from lipid peroxidation and environmental sources.

Accounts of chemical research ·Vol. 41 ·No. 7 ·2008-07-00 ·Pages 793-804

Stone MP, Cho YJ, Huang H, Kim HY, Kozekov ID, Kozekova A, Wang H, Minko IG, Lloyd RS, Harris TM, Rizzo CJ

Abstract

Significant levels of the 1, N(2)-gamma-hydroxypropano-dG adducts of the alpha,beta-unsaturated aldehydes acrolein, crotonaldehyde, and 4-hydroxy-2E-nonenal (HNE) have been identified in human DNA, arising from both exogenous and endogenous exposures. They yield interstrand DNA cross-links between guanines in the neighboring C.G and G.C base pairs located in 5'-CpG-3' sequences, as a result of opening of the 1,N(2)-gamma-hydroxypropano-dG adducts to form reactive aldehydes that are positioned within the minor groove of duplex DNA. Using a combination of chemical, spectroscopic, and computational methods, we have elucidated the chemistry of cross-link formation in duplex DNA. NMR spectroscopy revealed that, at equilibrium, the acrolein and crotonaldehyde cross-links consist primarily of interstrand carbinolamine linkages between the exocyclic amines of the two guanines located in the neighboring C.G and G.C base pairs located in 5'-CpG-3' sequences, that maintain the Watson-Crick hydrogen bonding of the cross-linked base pairs. The ability of crotonaldehyde and HNE to form interstrand cross-links depends upon their common relative stereochemistry at the C6 position of the 1,N(2)-gamma-hydroxypropano-dG adduct. The stereochemistry at this center modulates the orientation of the reactive aldehyde within the minor groove of the double-stranded DNA, either facilitating or hindering the cross-linking reactions; it also affects the stabilities of the resulting diastereoisomeric cross-links. The presence of these cross-links in vivo is anticipated to interfere with DNA replication and transcription, thereby contributing to the etiology of human disease. Reduced derivatives of these cross-links are useful tools for studying their biological processing.

MeSH Terms
Aldehydes/chemistry Amino Alcohols/chemistry Cross-Linking Reagents/chemistry DNA Adducts/chemistry Environment Lipid Peroxidation Magnetic Resonance Spectroscopy Models, Molecular Molecular Structure Oligonucleotides/chemistry Transition Temperature
Chemicals
Aldehydes Amino Alcohols Cross-Linking Reagents DNA Adducts Oligonucleotides
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Stone Michael P
Department of Chemistry, Center in Molecular Toxicology, and Vanderbilt Institute for Chemical Biology, Vanderbilt University, Nashville, Tennessee 37235, USA. [email protected]
Cho Young-Jin
Huang Hai
Kim Hye-Young
Kozekov Ivan D
Kozekova Albena
Wang Hao
Minko Irina G
Lloyd R Stephen
Harris Thomas M
Rizzo Carmelo J
References (68)
68 references, click to expand
  1. Stereospecific formation of interstrand carbinolamine DNA cross-links by crotonaldehyde- and acetaldehyde-derived alpha-CH3-gamma-OH-1,N2-propano-2'-deoxyguanosine adducts in the 5'-CpG-3' sequence.
    Chem Res Toxicol. 2006 Feb;19(2):195-208 PMID: 16485895
  2. The lipid peroxidation product 4-hydroxynonenal is a potent inducer of the SOS response.
    Mutat Res. 1992 Nov;293(1):1-10 PMID: 1383804
  3. Synthesis of nucleosides and oligonucleotides containing adducts of acrolein and vinyl chloride.
    Chem Res Toxicol. 2000 May;13(5):421-9 PMID: 10813660
  4. Stereocontrolled syntheses of all four stereoisomeric 1,N2-deoxyguanosine adducts of the lipid peroxidation product trans-4-hydroxynonenal.
    Org Lett. 2001 Nov 1;3(22):3603-5 PMID: 11678719
  5. NMR characterization of a DNA duplex containing the major acrolein-derived deoxyguanosine adduct gamma -OH-1,-N2-propano-2'-deoxyguanosine.
    J Biol Chem. 2001 Mar 23;276(12):9077-82 PMID: 11054428
  6. Kinetic and thermodynamic analysis of the hydrolytic ring-opening of the malondialdehyde-deoxyguanosine adduct, 3-(2'-deoxy-beta-D-erythro-pentofuranosyl)- pyrimido[1,2-alpha]purin-10(3H)-one.
    J Am Chem Soc. 2004 Jul 7;126(26):8237-43 PMID: 15225065
  7. Formation of cyclic adducts of deoxyguanosine with the aldehydes trans-4-hydroxy-2-hexenal and trans-4-hydroxy-2-nonenal in vitro.
    Cancer Res. 1986 Nov;46(11):5682-6 PMID: 3756915
  8. DNA interstrand crosslinks: natural and drug-induced DNA adducts that induce unique cellular responses.
    Chembiochem. 2005 Jan;6(1):27-32 PMID: 15637664
  9. Orientation of the crotonaldehyde-derived N2-[3-Oxo-1(S)-methyl-propyl]-dG DNA adduct hinders interstrand cross-link formation in the 5'-CpG-3' sequence.
    Chem Res Toxicol. 2006 Aug;19(8):1019-29 PMID: 16918240
  10. Identification and characterization of deoxyguanosine-crotonaldehyde adducts. Formation of 7,8 cyclic adducts and 1,N2,7,8 bis-cyclic adducts.
    Chem Res Toxicol. 1992 Nov-Dec;5(6):802-8 PMID: 1489932
  11. Detection and quantitation of acrolein-derived 1,N2-propanodeoxyguanosine adducts in human lung by liquid chromatography-electrospray ionization-tandem mass spectrometry.
    Chem Res Toxicol. 2007 Apr;20(4):565-71 PMID: 17385896
  12. Formation of cyclic 1,N2-propanodeoxyguanosine adducts in DNA upon reaction with acrolein or crotonaldehyde.
    Cancer Res. 1984 Mar;44(3):990-5 PMID: 6318992
  13. The Fanconi anemia/BRCA pathway: a coordinator of cross-link repair.
    Exp Cell Res. 2006 Aug 15;312(14):2647-53 PMID: 16859679
  14. 1,N2-deoxyguanosine adducts of acrolein, crotonaldehyde, and trans-4-hydroxynonenal cross-link to peptides via Schiff base linkage.
    J Biol Chem. 2003 Feb 21;278(8):5970-6 PMID: 12502710
  15. Synthesis of the minor acrolein adducts of 2(')-deoxyguanosine and their generation in oligomeric DNA.
    Bioorg Chem. 2003 Apr;31(2):136-48 PMID: 12729571
  16. Genotoxicity and mutagenicity of the alpha, beta-unsaturated carbonyl compound crotonaldehyde (butenal) on a plasmid shuttle vector.
    Mutat Res. 1998 Mar;407(2):125-34 PMID: 9637241
  17. Fanconi anemia and DNA replication repair.
    DNA Repair (Amst). 2007 Jul 1;6(7):885-90 PMID: 17481966
  18. Site-specific mutagenicity of stereochemically defined 1,N2-deoxyguanosine adducts of trans-4-hydroxynonenal in mammalian cells.
    Environ Mol Mutagen. 2003;42(2):68-74 PMID: 12929118
  19. Mutagenicity of 4-hydroxynonenal in V79 Chinese hamster cells.
    Mutat Res. 1987 Feb;190(2):169-71 PMID: 3821775
  20. Novel LC-ESI/MS/MS(n) method for the characterization and quantification of 2'-deoxyguanosine adducts of the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine by 2-D linear quadrupole ion trap mass spectrometry.
    Chem Res Toxicol. 2007 Feb;20(2):263-76 PMID: 17305409
  21. Induction of liver tumors in F344 rats by crotonaldehyde.
    Cancer Res. 1986 Mar;46(3):1285-9 PMID: 3002613
  22. Interchain cross-linking of DNA mediated by the principal adduct of acrolein.
    Chem Res Toxicol. 2001 Nov;14(11):1482-5 PMID: 11712904
  23. Stereospecific synthesis of oligonucleotides containing crotonaldehyde adducts of deoxyguanosine.
    Chem Res Toxicol. 2001 Nov;14(11):1506-12 PMID: 11712908
  24. Molecular analysis of mutations induced by acrolein in human fibroblast cells using supF shuttle vector plasmids.
    Mutat Res. 1998 Sep 11;417(2-3):65-73 PMID: 9733921
  25. Genotoxic lipid peroxidation products: their DNA damaging properties and role in formation of endogenous DNA adducts.
    Mutagenesis. 1998 May;13(3):287-305 PMID: 9643589
  26. Error prone translesion synthesis past gamma-hydroxypropano deoxyguanosine, the primary acrolein-derived adduct in mammalian cells.
    J Biol Chem. 2002 May 24;277(21):18257-65 PMID: 11889127
  27. On the reaction of guanine with glyoxal, pyruvaldehyde, and kethoxal, and the structure of the acylguanines. A new synthesis of N2-alkylguanines.
    Biochemistry. 1969 Jan;8(1):238-45 PMID: 5777326
  28. Fanconi anemia (cross)linked to DNA repair.
    Cell. 2005 Dec 29;123(7):1191-8 PMID: 16377561
  29. Stereochemistry modulates the stability of reduced interstrand cross-links arising from R- and S-alpha-CH3-gamma-OH-1,N2-propano-2'-deoxyguanosine in the 5'-CpG-3' DNA sequence.
    Biochemistry. 2007 Mar 13;46(10):2608-21 PMID: 17305317
  30. Site-specific synthesis and reactivity of oligonucleotides containing stereochemically defined 1,N2-deoxyguanosine adducts of the lipid peroxidation product trans-4-hydroxynonenal.
    J Am Chem Soc. 2003 May 14;125(19):5687-700 PMID: 12733907
  31. Naturally occurring carbonyl compounds are mutagens in Salmonella tester strain TA104.
    Mutat Res. 1985 Jan-Feb;148(1-2):25-34 PMID: 3881660
  32. Increased p53 mutation load in nontumorous human liver of wilson disease and hemochromatosis: oxyradical overload diseases.
    Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12770-5 PMID: 11050162
  33. Etheno-substituted nucleotides and coenzymes: fluorescence and biological activity.
    CRC Crit Rev Biochem. 1984;15(2):125-99 PMID: 6365449
  34. Deoxyguanosine adducts of t-4-hydroxy-2-nonenal are endogenous DNA lesions in rodents and humans: detection and potential sources.
    Cancer Res. 2000 Mar 15;60(6):1507-11 PMID: 10749113
  35. Formation and repair of interstrand cross-links in DNA.
    Chem Rev. 2006 Feb;106(2):277-301 PMID: 16464006
  36. Duplex DNA catalyzes the chemical rearrangement of a malondialdehyde deoxyguanosine adduct.
    Proc Natl Acad Sci U S A. 1999 Jun 8;96(12):6615-20 PMID: 10359760
  37. Structural studies of an oligodeoxynucleotide containing a trimethylene interstrand cross-link in a 5'-(CpG) motif: model of a malondialdehyde cross-link.
    J Am Chem Soc. 2001 Feb 28;123(8):1730-9 PMID: 11456774
  38. Incorporation of an aldehyde function in oligonucleotides.
    Bioconjug Chem. 2001 May-Jun;12(3):451-7 PMID: 11353544
  39. Endogenous formation and significance of 1,N2-propanodeoxyguanosine adducts.
    Mutat Res. 1999 Mar 8;424(1-2):71-81 PMID: 10064851
  40. Acrolein initiates rat urinary bladder carcinogenesis.
    Cancer Res. 1992 Jul 1;52(13):3577-81 PMID: 1617627
  41. NMR determination of the conformation of a trimethylene interstrand cross-link in an oligodeoxynucleotide duplex containing a 5'-d(GpC) motif.
    J Am Chem Soc. 2003 Jan 8;125(1):62-72 PMID: 12515507
  42. 1,N2-propanodeoxyguanosine adducts: potential new biomarkers of smoking-induced DNA damage in human oral tissue.
    Cancer Res. 1998 Feb 15;58(4):581-4 PMID: 9485001
  43. Acrolein mutagenicity in the V79 assay.
    Carcinogenesis. 1990 Mar;11(3):497-8 PMID: 2311195
  44. Mutagenesis of xeroderma pigmentosum fibroblasts by acrolein.
    Mutat Res. 1988 Sep-Oct;209(1-2):17-22 PMID: 3173398
  45. Multiple repair pathways mediate tolerance to chemotherapeutic cross-linking agents in vertebrate cells.
    Cancer Res. 2005 Dec 15;65(24):11704-11 PMID: 16357182
  46. Identification of DNA adducts of acetaldehyde.
    Chem Res Toxicol. 2000 Nov;13(11):1149-57 PMID: 11087437
  47. Detection of an interchain carbinolamine cross-link formed in a CpG sequence by the acrolein DNA adduct gamma-OH-1,N( 2)-propano-2'-deoxyguanosine.
    J Am Chem Soc. 2002 Aug 14;124(32):9324-5 PMID: 12166998
  48. The Fanconi Anemia/BRCA pathway: new faces in the crowd.
    Genes Dev. 2005 Dec 15;19(24):2925-40 PMID: 16357213
  49. Role of 1,N2-propanodeoxyguanosine adducts as endogenous DNA lesions in rodents and humans.
    IARC Sci Publ. 1999;(150):45-54 PMID: 10626207
  50. Postsynthetic generation of a major acrolein adduct of 2'-deoxyguanosine in oligomeric DNA.
    J Med Chem. 1999 Mar 25;42(6):947-50 PMID: 10090776
  51. Formation of cyclic 1,N2--adducts by reaction of deoxyguanosine with alpha-acetoxy-N-nitrosopyrrolidine, 4-(carbethoxynitrosamino)butanal, or crotonaldehyde.
    Cancer Res. 1983 Mar;43(3):1230-5 PMID: 6825094
  52. Mammalian cell mutagenesis of the DNA adducts of vinyl chloride and crotonaldehyde.
    Environ Mol Mutagen. 2005 Jun;45(5):455-9 PMID: 15690339
  53. Improved strategies for postoligomerization synthesis of oligodeoxynucleotides bearing structurally defined adducts at the N2 position of deoxyguanosine.
    Chem Res Toxicol. 1996 Apr-May;9(3):630-7 PMID: 8728509
  54. Lipid peroxidation-induced DNA damage in cancer-prone inflammatory diseases: a review of published adduct types and levels in humans.
    Free Radic Biol Med. 2007 Oct 15;43(8):1109-20 PMID: 17854706
  55. Reactions of alpha-acetoxy-N-nitrosopyrrolidine and crotonaldehyde with DNA.
    IARC Sci Publ. 1999;(150):147-54 PMID: 10626216
  56. DNA interchain cross-links formed by acrolein and crotonaldehyde.
    J Am Chem Soc. 2003 Jan 8;125(1):50-61 PMID: 12515506
  57. Quantification of N-(deoxyguanosin-8-yl)-4-aminobiphenyl adducts in human lymphoblastoid TK6 cells dosed with N-hydroxy-4-acetylaminobiphenyl and their relationship to mutation, toxicity, and gene expression profiling.
    Anal Chem. 2006 Sep 15;78(18):6422-32 PMID: 16970317
  58. Lipid peroxidation-DNA damage by malondialdehyde.
    Mutat Res. 1999 Mar 8;424(1-2):83-95 PMID: 10064852
  59. Characterization of thymidine adducts formed by acrolein and 2-bromoacrolein.
    Carcinogenesis. 1992 Dec;13(12):2361-5 PMID: 1473245
  60. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes.
    Free Radic Biol Med. 1991;11(1):81-128 PMID: 1937131
  61. LC/MS/MS method for the quantitation of trans-2-hexenal-derived exocyclic 1,N(2)-propanodeoxyguanosine in DNA.
    Chem Res Toxicol. 2006 Apr;19(4):563-70 PMID: 16608168
  62. Acrolein is a major cigarette-related lung cancer agent: Preferential binding at p53 mutational hotspots and inhibition of DNA repair.
    Proc Natl Acad Sci U S A. 2006 Oct 17;103(42):15404-9 PMID: 17030796
  63. Recognition between mitomycin C and specific DNA sequences for cross-link formation.
    Biochemistry. 1990 Mar 27;29(12):2999-3006 PMID: 2110821
  64. DNA adducts of acrolein: site-specific synthesis of an oligodeoxynucleotide containing 6-hydroxy-5,6,7,8-tetrahydropyrimido[1,2-a]purin-10(3H)-one, an acrolein adduct of guanine.
    Chem Res Toxicol. 2002 May;15(5):607-13 PMID: 12018980
  65. Spectroscopic characterization of interstrand carbinolamine cross-links formed in the 5'-CpG-3' sequence by the acrolein-derived gamma-OH-1,N2-propano-2'-deoxyguanosine DNA adduct.
    J Am Chem Soc. 2005 Dec 21;127(50):17686-96 PMID: 16351098
  66. Synthesis and properties of an acetaldehyde-derived oligonucleotide interstrand cross-link.
    Chem Res Toxicol. 2005 Apr;18(4):711-21 PMID: 15833031
  67. Site-specific synthesis of oligonucleotides containing malondialdehyde adducts of deoxyguanosine and deoxyadenosine via a postsynthetic modification strategy.
    Chem Res Toxicol. 2006 Nov;19(11):1467-74 PMID: 17112234
  68. Comparative evaluation of the bioreactivity and mutagenic spectra of acrolein-derived alpha-HOPdG and gamma-HOPdG regioisomeric deoxyguanosine adducts.
    Chem Res Toxicol. 2003 Aug;16(8):1019-28 PMID: 12924930
Article Info
Journal
Accounts of chemical research
Abbr.
Acc Chem Res
ISSN
1520-4898
DOI
10.1021/ar700246x
Email
[email protected]
Published
2008-07-00
Epub
2008-00-24
Pages
793-804
Language
English
Region
United States
NLM ID
0157313
PMCID
PMC2785109
Subset
IM
Grants
NIEHS NIH HHS · P01 ES-05355 · United States
NIEHS NIH HHS · P01 ES005355 · United States
NCRR NIH HHS · RR-05805 · United States
NIEHS NIH HHS · P30 ES000267 · United States
NIEHS NIH HHS · P01 ES005355-17 · United States
NIEHS NIH HHS · P30 ES-00267 · United States
External Links
PubMed source DOI: 10.1021/ar700246x PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2