Plant Monoterpenes Camphor, Eucalyptol, Thujone, and DNA Repair

  • Biljana NikolićEmail author
  • Dragana Mitić-Ćulafić
  • Branka Vuković-Gačić
  • Jelena Knežević-Vukčević
Reference work entry


Genotoxic and genoprotective effects of monoterpenes camphor, eucalyptol, and thujone were comparatively studied in bacterial and mammalian cells. In E. coli test system, low doses were antimutagenic against UV and 4NQO in the repair-proficient strain, but co-mutagenic in NER-deficient mutant. Additionally, they enhanced UV-induced SOS response and homologous recombination. However, high doses were mutagenic in NER- and MMR-deficient strains. Similarly, low doses decreased genotoxic effect of 4NQO in Vero cell line, while high doses were genotoxic. Genotoxicity was confirmed in human cell lines: fetal fibroblasts MRC-5 and colon carcinoma HT-29 and HCT116 cells.

Obtained results were consistent with hormesis phenomenon and indicated genotoxin-induced adaptive response provoked by low doses of monoterpenes: small amounts of DNA lesions evoked error-free DNA repair pathways, mainly NER, and provided protection against more potent genotoxic agents, such as UV and 4NQO. Adaptive response in E. coli is mediated by enhanced efficiency of NER during SOS induction. On the other hand, adaptive response in mammalian cells may involve transcriptional upregulation of NER genes DDB2, XPC, ERCC1, XPF, XPG, and LIG1 previously reported to be induced by UV. In addition, promotion of NER could involve UV-specific histone modifications, such as acetylation of H2A, H2B, H3, and H4, methylation of H3 and H4, and ubiquitination of H2A, H2B, H3, and H4.

Taking into account that numerous genotoxic agents induce DNA lesions repairable by NER, adaptive response provoked by camphor, eucalyptol, and thujone could be important for protection against environmental mutagens and carcinogens.


Monoterpenes Camphor Eucalyptol Thujone Escherichia coli model Mammalian cells Genotoxicity/antigenotoxicity DNA repair Hormesis phenomenon Genotoxin-induced adaptive response Nucleotide excision repair Transcriptional upregulation Histone modification 

List of Abbreviations


4-Nitroquinoline 1-oxide


Base excision repair


Double-strand break


Homologous recombination


Mismatch repair


Nucleotide excision repair


Nonhomologous end joining


Translesion synthesis



This work was supported by the Ministry of Education, Science and Technological Development of Republic of Serbia, Project No. 172058


  1. Aggarwal R, Jha M, Shrivastava A et al (2015) Natural compounds: role in reversal of epigenetic changes. Biochem Mosc 80:972–989CrossRefGoogle Scholar
  2. Bakkali F, Averbeck S, Averbeck D et al (2008) Biological effects of essential oils – a review. Food Chem Toxicol 46:446–475CrossRefGoogle Scholar
  3. Bannister AJ, Kouzarides T (2011) Regulation of chromatin by histone modifications. Cell Res 21:381–395CrossRefGoogle Scholar
  4. Bennett EJ, Harper JW (2008) DNA damage: ubiquitin marks the spot. Nat Struct Mol Biol 15:20–22CrossRefGoogle Scholar
  5. Berić T, Nikolić B, Stanojević J et al (2008) Protective effect of basil (Ocimum basilicum L.) against oxidative DNA damage and mutagenesis. Food Chem Toxicol 46:724–732CrossRefGoogle Scholar
  6. Bozkurt E, Atmaca H, Kisim A et al (2012) Effects of Thymus serpyllum extract on cell proliferation, apoptosis and epigenetic events in human breast cancer cells. Nutr Cancer 64:1245–1250CrossRefGoogle Scholar
  7. Bugarin D, Grbović S, Orčič D et al (2014) Essential oil of Eucalyptus gunnii hook. As a novel source of antioxidant, antimutagenic and antibacterial agents. Molecules 19:19007–19020CrossRefGoogle Scholar
  8. Busch C, Burkard M, Leischner C et al (2015) Epigenetic activities of flavonoids in the prevention and treatment of cancer. Clin Epigenetics 7:64. Scholar
  9. Calabrese EJ (2010) Hormesis is central to toxicology, pharmacology and risk assessment. Hum Exp Toxicol 29:249e261Google Scholar
  10. Camphausen K, Tofilon PJ (2007) Inhibition of histone deacetylation: a strategy for tumor radiosensitization. J Clin Oncol 25:4051–4056CrossRefGoogle Scholar
  11. Cao LL, Shen C, Zhu WG (2016) Histone modifications in DNA damage response. Sci China Life Sci 59:257–270CrossRefGoogle Scholar
  12. Carrier F, Georgel PT, Pourquier P et al (1999) Gadd45, a p53-responsive stress protein, modifies DNA accessibility on damaged chromatin. Mol Cell Biol 19:1673–1685CrossRefGoogle Scholar
  13. Christmann M, Kaina B (2013) Transcriptional regulation of human DNA repair genes following genotoxic stress: trigger mechanisms, inducible responses and genotoxic adaptation. Nucleic Acids Res 41:8403–8420CrossRefGoogle Scholar
  14. Ciccia A, Elledge SJ (2010) The DNA damage response: making it safe to play with knives. Mol Cell 40:179–204CrossRefGoogle Scholar
  15. Conde F, Refolio E, Cordon-Preciado V et al (2009) The Dot1 histone methyltransferase and the Rad9 checkpoint adaptor contribute to cohesin-dependent double-strand break repair by sister chromatid recombination in Saccharomyces cerevisiae. Genetics 182:437–446CrossRefGoogle Scholar
  16. Di Sotto A, Mazzanti G, Carbone F et al (2011) Genotoxicity of lavender oil, linalyl acetate, and linalool on human lymphocytes in vitro. Environ Mol Mutagen 52:69–71CrossRefGoogle Scholar
  17. Douglas P, Zhong J, Ye R et al (2010) Protein phosphatase 6 interacts with the DNA-dependent protein kinase catalytic subunit and dephosphorylates gamma-H2AX. Mol Cell Biol 30:1368–1381CrossRefGoogle Scholar
  18. Escargueil AE, Soares DG, Salvador M et al (2008) What histone code for DNA repair? Mutat Res 658:259–270CrossRefGoogle Scholar
  19. Fernandez-Capetillo O, Allis CD, Nussenzweig A (2004) Phosphorylation of histone H2B at DNA double-strand breaks. J Exp Med 199:1671–1677CrossRefGoogle Scholar
  20. Fnu S, Williamson EA, De Haro LP et al (2011) Methylation of histone H3 lysine 36 enhances DNA repair by nonhomologous end-joining. P Natal Acad Sci USA 108:540–545CrossRefGoogle Scholar
  21. Fradet-Turcotte A, Canny MD, Escribano-Diaz C et al (2013) 53BP1 is a reader of the DNA-damage-induced H2A Lys 15 ubiquitin mark. Nature 499:50–54CrossRefGoogle Scholar
  22. Guo R, Chen J, Mitchell DL et al (2011) GCN5 and E2F1 stimulate nucleotide excision repair by promoting H3K9 acetylation at sites of damage. Nucleic Acids Res 39:1390–1397CrossRefGoogle Scholar
  23. Hunt CR, Ramnarain D, Horikoshi N et al (2013) Histone modifications and DNA double-strand break repair after exposure to ionizing radiations. Radiat Res 179:383–392CrossRefGoogle Scholar
  24. Ko HL, Ren EC (2012) Functional aspects of PARP1 in DNA repair and transcription. Biomol Ther 2:524–548Google Scholar
  25. Kocaman AY, Rencüzoǧullari E, Topaktaş M et al (2011) The effects of 4-thujanol on chromosome aberrations, sister chromatid exchanges and micronucleus in human peripheral blood lymphocytes. Cytotechnology 63:493–502CrossRefGoogle Scholar
  26. Koh KH, Kang HJ, Li LS et al (2005) Impaired nonhomologous end-joining in mismatch repair-deficient colon carcinomas. Lab Investig 85:1130–1138CrossRefGoogle Scholar
  27. Lahtz C, Pfeifer GP (2011) Epigenetic changes of DNA repair genes in cancer. J Mol Cell Biol 3:51–58CrossRefGoogle Scholar
  28. Lee JS, Smith E, Shilatifard A (2010) The language of histone crosstalk. Cell 142:682–685CrossRefGoogle Scholar
  29. Li S (2012) Implication of posttranslational histone modifications in nucleotide excision repair. J Mol Sci 13:12461–12486CrossRefGoogle Scholar
  30. Mimica-Dukić N, Bugarin D, Grbović S et al (2010) Essential oil of Myrtus communis L. as a potential antioxidant and antimutagenic agents. Molecules 15:2759–2770CrossRefGoogle Scholar
  31. Mitić-Ćulafić D, Žegura B, Nikolić B et al (2009) Protective effect of linalool, myrcene and eucalyptol against t-butyl hydroperoxide induced genotoxicity in bacteria and cultured human cells. Food Chem Tox 47:260–266CrossRefGoogle Scholar
  32. Niehrs C, Schäfer A (2012) Active DNA demethylation by Gadd45 and DNA repair. Trends Cell Biol 22:220–227CrossRefGoogle Scholar
  33. Nikolić B, Jovanović B, Mitić-Ćulafić D et al (2015) Comparative study of genotoxic, antigenotoxic and cytotoxic activities of monoterpenes camphor, eucalyptol and thujone in bacteria and mammalian cells. Chem Biol Interact 242:263–271CrossRefGoogle Scholar
  34. Nikolić B, Mitić-Ćulafić D, Stajković-Srbinović O et al (2012) Effect of metabolic transformation of monoterpenes on antimutagenic potential in bacterial tests. Arch Biol Sci 64:885–894CrossRefGoogle Scholar
  35. Nikolić B, Mitić-Ćulafić D, Vuković-Gačić B et al (2011a) The antimutagenic effect of monoterpenes against UV-irradiation-, 4NQO- and t-BOOH-induced mutagenesis in E. coli. Arch BiolSci 63:117–128CrossRefGoogle Scholar
  36. Nikolić B, Mitić-Ćulafić D, Vuković-Gačić B et al (2011b) Modulation of genotoxicity and DNA repair by plant monoterpenes camphor, eucalyptol and thujone in Escherichia coli and mammalian cells. Food Chem Toxicol 49:2035–2045CrossRefGoogle Scholar
  37. Panier S, Boulton SJ (2014) Double-strand break repair: 53BP1 comes into focus. Nat Rev Mol Cell Bio 15:7–18CrossRefGoogle Scholar
  38. Pelkonen O, Abass K, Wiesner J (2013) Thujone and thujone-containing herbal medicinal and botanical products: toxicological assessment. Regul Toxicol Pharmacol 65:100–107CrossRefGoogle Scholar
  39. Sancar A, Lindsey-Boltz LA, Unsal-Kacmaz K et al (2004) Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu Rev Biochem 73:39–85CrossRefGoogle Scholar
  40. Sasaki T, Lynch KL, Mueller CV et al (2014) Heterochromatin controls gammaH2A localization in Neurospora crassa. Eukaryot Cell 13:990–1000CrossRefGoogle Scholar
  41. Schlade-Bartusiak K, Stembalska-Kozlowska A, Bernady M et al (2002) Analysis of adaptive response to bleomycin and mitomycin C. Mutat Res 513:75–81CrossRefGoogle Scholar
  42. Simić D, Vuković-Gačić B, Knežević-Vukčević J (1998) Detection of natural bioantimutagens and their mechanisms of action with bacterial assay-system. Mutat Res 402:51–57CrossRefGoogle Scholar
  43. Smith ML, Ford JM, Hollander MC et al (2000) p53-mediated DNA repair responses to UV radiation: studies of mouse cells lacking p53, p21, and/or gadd45 genes. Mol Cell Biol 20:3705–3714CrossRefGoogle Scholar
  44. Stajković O, Berić-Bjedov T, Mitić-Ćulafić D et al (2007) Antimutagenic properties of basil (Ocimum basilicum L.) in Salmonella typhimurium TA100. Food Technol Biotehnol 45:213–217Google Scholar
  45. Surh Y-J (2011) Xenohormesis mechanisms underlying chemopreventive effects of some dietary phytochemicals. Ann N Y Acad Sci 1229:1–6CrossRefGoogle Scholar
  46. Tatum D, Li S (2011) Evidence that the histone methyltransferase Dot1 mediates global genomic repair by methylating histone H3 on lysine 79. J Biol Chem 286:17530–17535CrossRefGoogle Scholar
  47. Tjeertes JV, Mille KM, Jackson SP (2009) Screen for DNA-damage-responsive histone modifications identifies H3K9Ac and H3K56Ac in human cells. EMBO J 28:1878–1889CrossRefGoogle Scholar
  48. Tomicic MT, Reischmann P, Rasenberger B et al (2011) Delayed c-Fos activation in human cells triggers XPF induction and an adaptive response to UVC-induced DNA damage and cytotoxicity. Cell Mol Life Sci 68:1785–1798CrossRefGoogle Scholar
  49. Truglio JJ, Croteau DL, VanHouten B et al (2006) Prokaryotic nucleotide excision repair: the UvrABC system. Chem Rev 106:233–252CrossRefGoogle Scholar
  50. Utley RT, Lacoste N, Jobin-Robitaille O et al (2005) Regulation of NuA4 histone acetyltransferase activity in transcription and DNA repair by phosphorylation of histone H4. Mol Cell Biol 25:8179–8190CrossRefGoogle Scholar
  51. Vuković-Gačić B, Nikčević S, Berić-Bjedov T et al (2006) Antimutagenic effect of essential oil of sage (Salvia officinalis L.) and its monoterpenes against UV-induced mutations in Escherichia coli and Saccharomyces cerevisiae. Food Chem Toxicol 44:1730–1738CrossRefGoogle Scholar
  52. Wolff S, Afzal V, Wiencke JK et al (1988) Human lymphocytes exposed to low doses of ionizing radiations become refractory to high doses of radiation as well as to chemical mutagens that induce double-strand breaks in DNA. Int J Radiat Biol Relat Stud Phys Chem Med 53:39–47CrossRefGoogle Scholar
  53. Wu W, Nishikawa H, Fukuda T et al (2015) Interaction of BARD1 and HP1 is required for BRCA1 retention at sites of DNA damage. Cancer Res 75:1311–1321CrossRefGoogle Scholar
  54. Ye N, Bianchi MS, Bianchi NO et al (1999) Adaptive enhancement and kinetics of nucleotide excision repair in humans. Mutat Res 435:43–61CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Biljana Nikolić
    • 1
    Email author
  • Dragana Mitić-Ćulafić
    • 1
  • Branka Vuković-Gačić
    • 1
  • Jelena Knežević-Vukčević
    • 1
  1. 1.Microbiology, Center for Genotoxicology and EcogenotoxicologyFaculty of Biology, University of BelgradeBelgradeSerbia

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