Mutagenic and carcinogenic structural alerts and their mechanisms of action

Open access

Abstract

Knowing the mutagenic and carcinogenic properties of chemicals is very important for their hazard (and risk) assessment. One of the crucial events that trigger genotoxic and sometimes carcinogenic effects is the forming of adducts between chemical compounds and nucleic acids and histones. This review takes a look at the mechanisms related to specific functional groups (structural alerts or toxicophores) that may trigger genotoxic or epigenetic effects in the cells. We present up-to-date information about defined structural alerts with their mechanisms and the software based on this knowledge (QSAR models and classification schemes).

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • 1. Benigni R Bossa C. Structure alerts for carcinogenicity and the Salmonella assay system: A novel insight through the chemical relational database technology. Mutat Res 2008;659:248-61. doi:

    • Crossref
    • Export Citation
  • 2. Benigni R Bossa C. Structural Alerts of mutagens and cacinogens. Curr Comput - Aid Drug Design 2006;2:169-76. doi:

    • Crossref
    • Export Citation
  • 3. Farmer PB. DNA and protein adducts as markers of genotoxicity. Toxicol Lett 2004;149:3-9. doi:

    • Crossref
    • Export Citation
  • 4. Powell CL Swenberg JA Rusyn I. Expression of base excision DNA repair genes as a biomarker of oxidative DNA damage. Cancer Lett 2005;229:1-11. doi:

    • Crossref
    • Export Citation
  • 5. Klaunig J Wang Z Pu X Zhou S. Oxidative stress and oxidative damage in chemical carcinogensesis. Toxicol Appl Phramacol 2011;254:86-99. doi:

    • Crossref
    • Export Citation
  • 6. Pulliero A Godschalk R Andreassi MG Curfs D Van Schooten FJ Izzotti A. Environmental carcinogens and mutational pathways in atherosclerosis. Int J Hyg Environ Health 2015;218:293-312. doi:

    • Crossref
    • Export Citation
  • 7. Tanaka T Shimizu M Kochi T Moriwaki H. Chemicalinduced carcinogenesis. J Exp Clin Med 2013;5:203-9. doi:

    • Crossref
    • Export Citation
  • 8. Helguera AM Cordeiro N Perez MA. Combes R Perez Gonzales M. QSAR modeling of the rodent carcinogenicity of nitrocompounds. Bioorg Med Chem 2008;16:3395-407. doi:

    • Crossref
    • Export Citation
  • 9. Gonzales-Perez M Gomez-Bombarelli R Arenas-Valganon J Perez-Prior T Garcia-Santos P Calle E Casado J. Connecting the chemical and biological reactivity of epoxides. Chem Res Toxicol 2012;25:2755-62. doi:

    • Crossref
    • Export Citation
  • 10. Zhang S Chen K Aliaga C Sun Y Lin J Sharma A Amin S El-Bayoumy K. Identification and quantification of DNA adducts in the oral tissues of mice treated with the environmental carcinogen dibenzo[al]pyrene by HPLC-MS/ MS. Chem Res Toxicol 2011;24:1297-303. doi:

    • Crossref
    • Export Citation
  • 11. Miller E Miller C. Searches for ultimate chemical carcinogens and their reactions with cellular macromolecules. Cancer 1981;47:2327-45. PMID: 7272889

  • 12. La DK Swenberg JA. DNA adducts: biological markers of exposure and potential applications to risk assesment. Mutat Res 1996;365:129-46. doi:

    • Crossref
    • Export Citation
  • 13. Schwaab S Czich A Epe B Kaina B Müller L Pollet D Utesch D. Photochemical genotoxicity: principles and test methods: Report of a GUM task force. Mutat Res 2004;566:65-91. doi:

    • Crossref
    • Export Citation
  • 14. Epe B. DNA damage spectra induced by photosensitization. Photochem Photobiol Sci 2012;11:98-106. doi:

    • Crossref
    • Export Citation
  • 15. Spielmann H Lovell W Hoelzle E. In vitro phototoxicity testing. The report and recommendations of ECVAM workshop 2. ATLA 1994;22:314-48.

  • 16. Dennehy M Richards K Wernke G Shyr Y Liebler D. Cytosolic and nuclear protein targets of thiol-reactive electrophiles. Chem Res Toxicol 2006;19:20-9. doi:

    • Crossref
    • Export Citation
  • 17. Schultz W Yarbrough J Hunter R Aptula A. Verification of the structural alerts for Michael acceptors. Chem Res Toxicol 2007;20:1359-63. doi:

    • Crossref
    • Export Citation
  • 18. Delaney J Essgmann J. Biological properties of single chemical-DNA adducts: a twenty year perspective. Chem Res Toxicol 2008;21:232-52. doi:

    • Crossref
    • Export Citation
  • 19. Drinkwater NR Miller JA Miller EC Yang N-C. Covalent intercalate binding to DNA in relation to the mutagenicity of hydrocarbon epoxides and N-acetoxy-2-acetylaminofluorene. Cancer Res 1978;38:3247-55. PMID: 356963

  • 20. Ketterer B Coles B Meyer DJ. The role of glutathione in detoxication. Environ Healt Persp 1983;49:59-69. PMCID: PMC1569131

  • 21. Yan Z Maher N Torres R Huebert N. Use of a trapping agent for simultaneous capturing and high-throughput screening of both “soft” and “hard” reactive metabolites. Anal Chem 2007;79:4206-14. doi:

    • Crossref
    • Export Citation
  • 22. Zang H Gates KS. Sequence specificity of DNA alkylation by the antitumor natural product leinamycin. Chem Res Toxicol 2003;16:1539-46. doi:

    • Crossref
    • Export Citation
  • 23. Allgayer H Kolb M Stuber V Kruis W. Modulation of base hydroxylation by bile acids and salicylate s in a model of human colonic mucosal DNA putative implications in colonic cancer. DigDisSci 1999; 44: 761 - 7. doi:

    • Crossref
    • Export Citation
  • 24. Benigni R Bossa C Jeliazkova N Netzeva T Worth A. The Benigni/Bossa rulebase for mutagenicity and carcinogenicity-a module of Toxtree 2008 [displayed 28 July 2016]. Available at https://eurl-ecvam.jrc.ec.europa.eu/laboratories-research/predictive_toxicology/doc/EUR_23241_EN.pdf

  • 25. Snodin D. Genotoxic impurities: from structural alerts to qualification. Org Proc Res Develop 2010;14:960-76. doi:

    • Crossref
    • Export Citation
  • 26. Ellison CM Sherhod R Cronin MTD Enoch SJ. Madden JC Judson PN. Assessment of methods to define the applicability domain of structural alert models. J Chem Inf Model 2011;51:975-85. doi:

    • Crossref
    • Export Citation
  • 27. Kazius J McGuire R Bursi R. Derivation and validation of toxicophores for mutagenicity prediction. J Med Chem 2005;48:312-20. doi:

    • Crossref
    • Export Citation
  • 28. Benigni R Bossa C Tcheremenskaia O. Nongenotoxic carcinogenicity of chemicals: mechanisms of action and early recognition through a new set of structural alerts. Chem Rev 2013;113:2940-57. doi:

    • Crossref
    • Export Citation
  • 29. Goetz ME Luch A. Reactive species: A cell damaging rout assisting to chemical carcinogens. Cancer Lett 2008;266:73-83. doi:

    • Crossref
    • Export Citation
  • 30. Enoch SJ Cronin M. Development of new structural alerts suitable for chemical category formation for assigning covalent and non-covalent mechanisms relevant to DNA binding. Mutat Res 2012;743:10-9. doi:

    • Crossref
    • Export Citation
  • 31. Schwöbel JA Koleva Y Enoch S Bajot F Hewitt M Madden JC Roberts DW Schultz TW Cronin MT. Measurement and estimation of electrophilic reactivity for predictive toxicology. Chem Rev 2011;111:2562-96. doi:

    • Crossref
    • Export Citation
  • 32. Nash HM Rongzhen L Lane WS Verdinel GL. The critical active-site amine of the human 8-oxoguanine DNA glycosylase hOgg1: direct identification ablation and chemical reconstitution. Chem Biol 1997;4:693-702. doi:

    • Crossref
    • Export Citation
  • 33. Enoch SJ Cronin MTD Ellison CM. The use of a chemistrybased profiler for covalent DNA binding in the development of chemical categories for read-across for genotoxicity. ATLA 2011;39:131-45. PMID: 21639678

  • 34. Enoch SJ Cronin MTD. A review of the electrophilic reaction chemistry involved in covalent DNA binding. Crit Rev Toxicol 2010;40:728-48. doi:

    • Crossref
    • Export Citation
  • 35. Kolšek K Sollner Dolenc M Mavri J. Computational study of the reactivity of bisphenol A-34-quinone with deoxyadenosine and glutathione. Chem Res Toxicol 2013;26:106-11. doi:

    • Crossref
    • Export Citation
  • 36. Garner RC. The role of DNA adducts in chemical carcinogenesis. Mutat Res 1988;402:67-75. doi:

    • Crossref
    • Export Citation
  • 37. Henkler F Stolpmann K Luch A. Exposure to polycyclic aromatic hydrocarbons: Bulky DNA adducts and cellular responses. Mol Clin Environ Toxicol 2012;101:107-31. doi:

    • Crossref
    • Export Citation
  • 38. Veglia F Matullo G Vineis P. Bulky DNA adducts and risk of cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev 2003;12:157-60. PMID: 12582026

  • 39. Mukherjee A Lavery R Bagchi B Hyne JT. On the molecular mechanism of drug intercalation into DNA: A simulation study of the intercalation pathway free energy and DNA structural changes. J Am Chem Soc 2008;130:9747-55. doi:

    • Crossref
    • Export Citation
  • 40. Jałoszyński P Jaruga P Oliński R Biczysko W Szyfter W Nagy E Möller L Szyfter K. Oxidative DNA base modifications and polycyclic aromatic hydrocarbon DNA adducts in squamous cell carcinoma of larynx. Free Radic Res 2003;37:231-40. doi:

    • Crossref
    • Export Citation
  • 41. Lenne-Samuel N Janel-Bintz R Kolbanovskiy A Geacintov NE Fuchs RP. The processing of a Benzo(a)pyrene adduct into a frameshift or a base substitution mutation requires a different set of genes in Escherichia coli. Mol Microbiol 2000;38:299-307. doi:

    • Crossref
    • Export Citation
  • 42. Heidrun Ellinger-Ziegelbauer H Stuart B Wahle B Werner B Juergen AH. Comparison of the expression profiles induced by genotoxic and nongenotoxic carcinogens in rat liver. Mutat Res 2005;575:61-84. doi:

    • Crossref
    • Export Citation
  • 43. Butterworth EB. A classification framework and practical guidance for establishing a mode of action for chemical carcinogens. Regul Toxicol Pharmacol 2006;45:9-23. doi:

    • Crossref
    • Export Citation
  • 44. Marnett LJ Burcham PC. Endogenous DNA adducts: potential and paradox. Chem Res Toxicol 1993;6:771-85. doi:

    • Crossref
    • Export Citation
  • 45. Wiseman H Kaur H Halliwell B. DNA damage and cancer: measurement and mechanism. Cancer Lett 1995;93:113-20. doi:

    • Crossref
    • Export Citation
  • 46. Kulis M Esteller M. DNA methylation and cancer. Adv Genet 2010;70:27-56. doi:

    • Crossref
    • Export Citation
  • 47. Ehrlich M. DNA methylation in cancer: too much but also too little. Oncogene 2010;21:5400-13. doi:

    • Crossref
    • Export Citation
  • 48. Ropero S Esteller M. The role of histone deacetylases (HDACs) in human cancer. Mol Oncol 2007;1:19-25. doi:

    • Crossref
    • Export Citation
  • 49. Polo SE. Almouzni G. Histone metabolic pathways and chromatin assembly factors as proliferation markers. Cancer Lett 2005:220:1-9. doi:

    • Crossref
    • Export Citation
  • 50. Momparler RL. Cancer epigenetics. Oncogene 2003;22:6479-83. doi:

    • Crossref
    • Export Citation
  • 51. Klaunig JE Xu Y Isenberg JS Bachowski S Kolaja KL Jiang J Stevenson DE Walborg EF. The role of oxidative stress in chemical carcinogenesis. Environ Health Perspect 1998;106:289-95. doi:

    • Crossref
    • Export Citation
  • 52. Crews D McLachlan JA. Epigenetic evolution endocrine disruption health and disease. Endocrinology 2006;147(6 Suppl):S4-10. doi:

    • Crossref
    • Export Citation
  • 53. Darbre PD. Environmental oestrogens cosmetics and breast cancer. Best Pract Res Clin Endocrinol Metab 2006;20:121-43. doi:

    • Crossref
    • Export Citation
  • 54. Birnbaum LS Fenton SE. Cancer and developmental exposure to endocrine disruptors. Environ Health Perspect 2003;111:389-94. PMCID: PMC1241417

  • 55. Choi SM Yoo SD Lee BM. Toxicological charactersistics of endocrine-disrupting chemicals: developmental toxicity carcinogenicity and mutagenicity. J Toxicol Environ Health 2004;7:1-23. doi:

    • Crossref
    • Export Citation
  • 56. Harvey PW Johnson I. Approaches to the assessment of toxicology data with endpoints related to endocrine disruption. J Appl Toxicol 2002;22:241-7. doi:

    • Crossref
    • Export Citation
  • 57. Zhong M Nie X Yan A Yuan Q. (2013) Carcinogenicity prediction of noncongeneric chemicals by a support vector machine. Chem Res Toxicol 2013;26:741-9. doi:

    • Crossref
    • Export Citation
  • 58. Plošnik A Zupan J Vračko M. Evaluation of toxic endpoints for a set of cosmetic ingredients with CAESAR models. Chemosphere 2015;120:492-9. doi:

    • Crossref
    • Export Citation
  • 59. Ferrari T Gini G. An open source multistep model to predict mutagenicity from statistical analysis and relevant structural alerts. Chem Cent J 2010;4:1-6. doi:

    • Crossref
    • Export Citation
  • 60. Cariello N F Wilson JD Britt BH Wedd DJ Burlinson B Gombar V. Comparison of the computer programs DEREK and TOPKAT to predict bacterial mutagenicity. Mutagenesis 2002;17:321-9. doi:

    • Crossref
    • Export Citation
  • 61. Serafimova R Gatnik FM Worth A. Review of QSAR models and software tools for predicting genotoxicity and carcinogenicity 2010 [displayed 29 July 2016]. Available at https://eurl-ecvam.jrc.ec.europa.eu/laboratories-research/predictive_toxicology/doc/EUR_24427_EN.pdf

  • 62. Klopman G. The MultiCASE program II. Baseline activity identification algorithm (BAIA). J Chem Inf Comput Sci 1998;38:78-81. doi:

    • Crossref
    • Export Citation
  • 63. QSAR Toolbox User Manual [displayed 17 April 2015]. Available at http://www.oecd.org/chemicalsafety/riskassessment/TB3%200_GettingStarted_rev2.pdF

  • 64. Ideaconsult. Toxtree User Manual [displayed 17 April 2015]. Available at https://eurl-ecvam.jrc.ec.europa.eu/laboratoriesresearch/predictive_toxicology/doc/Toxtree_user_manual.pdf

  • 65. Helma C. Lazy structure-activity relationships (LAZAR) for the prediction of rodent carcinogenicity and Salmonella mutagenicity. Mol Divers 2006;10:147-58. doi:

    • Crossref
    • Export Citation
  • 66. Maunz A Gütlein M Rautenberg M Vorgrimmler D Gebele D Helma C. LAZAR: a modular predictive toxicology framework. Front Pharmacol 2013;4:1-8. doi:

    • Crossref
    • Export Citation
  • 67. Worth A Lapenna S Lo Piparo E Mostrag-Szlichtyng A Serafimova R. A framework for assessing in silico toxicity predictions: case studies with selected pesticides. JRC report EUR 24705 EN 2011.

  • 68. Leadscope webpage [displayed 19 February 2016]. Available at http://www.leadscope.com

Search
Journal information
Impact Factor

IMPACT FACTOR 2018: 1.436
5-year IMPACT FACTOR: 1.606

CiteScore 2018: 1.53

SCImago Journal Rank (SJR) 2018: 0.358
Source Normalized Impact per Paper (SNIP) 2018: 0.608

Cited By
Metrics
All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 551 380 88
PDF Downloads 336 252 48