Skip to main content
SpringerLink
Log in

Chronic Ethanol Consumption and Generation of Etheno-DNA Adducts in Cancer-Prone Tissues

  • Conference paper
  • First Online:
Alcohol and Cancer

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1032))

Abstract

Chronic ethanol consumption is a risk factor for several human cancers. A variety of mechanisms may contribute to this carcinogenic effect of alcohol including oxidative stress with the generation of reactive oxygen species (ROS), formed via inflammatory pathways or as byproducts of ethanol oxidation through cytochrome P4502E1 (CYP2E1). ROS may lead to lipidperoxidation (LPO) resulting in LPO-products such as 4-hydoxynonenal (4-HNE) or malondialdehyde. These compounds can react with DNA bases forming mutagenic and carcinogenic etheno-DNA adducts. Etheno-DNA adducts are generated in the liver (HepG2) cells over-expressing CYP2E1 when incubated with ethanol;and are inhibited by chlormethiazole. In liver biopsies etheno-DNA adducts correlated significantly with CYP2E1. Such a correlation was also found in the esophageal- and colorectal mucosa of alcoholics. Etheno-DNA adducts also increased in liver biopsies from patients with non alcoholic steatohepatitis (NASH). In various animal models with fatty liver either induced by high fat diets or genetically modified such as in the obese Zucker rat, CYP2E1 is induced and paralleled by high levels of etheno DNA-adducts which may be modified by additional alcohol administration. As elevation of adduct levels in NASH children were already detected at a young age, these lesions may contribute to hepatocellular cancer development later in life. Together these data strongly implicate CYP2E1 as an important mediator for etheno-DNA adduct formation, and this detrimental DNA damage may act as a driving force for malignant disease progression.

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 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
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

  1. Bardag-Gorce F, Oliva J, Dedes J, Li J, French BA, French SW (2009) Chronic ethanol feeding alters hepatocyte memory which is not altered by acute feeding. Alcohol Clin Exp Res 33(4):684–692

    Article  CAS  Google Scholar 

  2. Bartsch H, Nair J (2005) Accumulation of lipid peroxidation-derived DNA lesions: potential lead markers for chemoprevention of inflammation-driven malignancies. Mutat Res 591(1–2):34–44

    Article  CAS  Google Scholar 

  3. Bartsch H, Nair J (2014) Lipid peroxidation-derived DNA adduts and the role in inflammation-related carcinogenesis. In: Hiraku Y, Kawanishi S, Ohshima H (eds) Cancer and inflammation mechanisms chemical, biological and clinical aspects. Wiley, Hoboken, pp 61–74

    Chapter  Google Scholar 

  4. Frank A, Seitz HK, Bartsch H et al (2004) Immunohistochemical detection of 1,N6-ethenodeoxyadenosine in nuclei of human liver affected by diseases predisposing to hepato-carcinogenesis. Carcinogenesis 25(6):1027–1031

    Article  CAS  Google Scholar 

  5. Bartsch H (1999) Keynote address: exocyclic adducts as new risk markers for DNA damage in man. IARC Sci Publ 150:1–16

    CAS  Google Scholar 

  6. Bartsch H, Nair J (2004) Oxidative stress and lipid peroxidation-derived DNA-lesions in inflammation driven carcinogenesis. Cancer Detect Prev 28(6):385–391

    Article  CAS  Google Scholar 

  7. Nair J, Srivatanakul P, Haas C et al (2010) High urinary excretion of lipid peroxidation-derived DNA damage in patients with cancer-prone liver diseases. Mutat Res 683(1–2):23–28

    Article  CAS  Google Scholar 

  8. Nair J, Furstenberger G, Burger F et al (2000) Promutagenic etheno-DNA adducts in multistage mouse skin carcinogenesis: correlation with lipoxygenase-catalyzed arachidonic acid metabolism. Chem Res Toxicol 13(8):703–709

    Article  CAS  Google Scholar 

  9. Marks F, Muller-Decker K, Furstenberger G (2000) A causal relationship between unscheduled eicosanoid signaling and tumor development: cancer chemoprevention by inhibitors of arachidonic acid metabolism. Toxicology 153(1–3):11–26

    Article  CAS  Google Scholar 

  10. Williams CS, Luongo C, Radhika A et al (1996) Elevated cyclooxygenase-2 levels in min mouse adenomas. Gastroenterology 111(4):1134–1140

    Article  CAS  Google Scholar 

  11. Williams MV, Lee SH, Pollack M et al (2006) Endogenous lipid hydroperoxide-mediated DNA-adduct formation in min mice. J Biol Chem 281(15):10127–10133

    Article  CAS  Google Scholar 

  12. Schmid K, Nair J, Winde G et al (2000) Increased levels of promutagenic etheno-DNA adducts in colonic polyps of FAP patients. Int J Cancer 87(1):1–4

    Article  CAS  Google Scholar 

  13. Linhart K, Bartsch H, Seitz HK (2014) The role of reactive oxygen species (ROS) and cytochrome P-450 2E1 in the generation of carcinogenic etheno-DNA adducts. Redox Biol 3:56–62

    Article  CAS  Google Scholar 

  14. Linhart KB, Glassen K, Peccerella T et al (2015 Apr) The generation of carcinogenic etheno-DNA adducts in the liver of patients with nonalcoholic fatty liver disease. Hepatobiliary Surg Nutr 4(2):117–123

    PubMed  PubMed Central  Google Scholar 

  15. Winter CK, Segall HJ, Haddon WF (1986) Formation of cyclic adducts of deoxyguanosine with the aldehydes trans-4-hydroxy-2-hexenal and trans-4-hydroxy-2-nonenal in vitro. Cancer Res 46(11):5682–5686

    CAS  PubMed  Google Scholar 

  16. Chung FL, Chen HJ, Nath RG (1996) Lipid peroxidation as a potential endogenous source for the formation of exocyclic DNA adducts. Carcinogenesis 17(10):2105–2111

    Article  CAS  Google Scholar 

  17. el Ghissassi F, Barbin A, Nair J et al (1995) Formation of 1,N6-ethenoadenine and 3,N4-ethenocytosine by lipid peroxidation products and nucleic acid bases. Chem Res Toxicol 8(2):278–283

    Article  Google Scholar 

  18. Vaca CE, Wilhelm J, Harms-Ringdahl M (1988) Interaction of lipid peroxidation products with DNA. A Rev Mutat Res 195(2):137–149

    Article  CAS  Google Scholar 

  19. Pryor WA, Porter NA (1990) Suggested mechanisms for the production of 4-hydroxy-2-nonenal from the autoxidation of polyunsaturated fatty acids. Free Radic Biol Med 8(6):541–543

    Article  CAS  Google Scholar 

  20. Blair IA (2008) DNA adducts with lipid peroxidation products. J Biol Chem 283(23):15545–15549

    Article  CAS  Google Scholar 

  21. Sodum RS, Chung FL (1991) Stereoselective formation of in vitro nucleic acid adducts by 2,3-epoxy-4-hydroxynonanal. Cancer Res 51(1):137–143

    CAS  PubMed  Google Scholar 

  22. Nair U, Bartsch H, Nair J (2007) Lipid peroxidation-induced DNA damage in cancer-prone inflammatory diseases: a review of published adduct types and levels in humans. Free Radic Biol Med 43(8):1109–1120

    Article  CAS  Google Scholar 

  23. Hiraku Y, Kawanishi S (2014) Role of nitrative DNA damage in inflammation related carcinogenesis. In: Ohshima H (ed) Cancer and INflammation mechanisms: chemical, biological, and chemical aspects. Wiley, Hoboken, pp 41–59

    Chapter  Google Scholar 

  24. Eberle G, Barbin A, Laib RJ et al (1989) 1,N6-etheno-2′-deoxyadenosine and 3,N4-etheno-2′-deoxycytidine detected by monoclonal antibodies in lung and liver DNA of rats exposed to vinyl chloride. Carcinogenesis 10(1):209–212

    Article  CAS  Google Scholar 

  25. Nair J, Nair UJ, Sun X et al (2010) Quantifying etheno-DNA adducts in human tissues, white blood cells, and urine by ultrasensitive (32)P-postlabeling and immunohistochemistry. Methods Mol Biol 682:189–205

    Article  Google Scholar 

  26. Nair J, Barbin A, Guichard Y et al (1995) 1,N6-ethenodeoxyadenosine and 3,N4-ethenodeoxycytine in liver DNA from humans and untreated rodents detected by immunoaffinity/32P-postlabeling. Carcinogenesis 16(3):613–617

    Article  CAS  Google Scholar 

  27. Nair J, Godschalk RW, Nair U et al (2011) Identification of 3,N(4)-etheno-5-methyl-2′-deoxycytidine in human DNA: a new modified nucleoside which may perturb genome methylation. Chem Res Toxicol 25(1):162–169

    Article  Google Scholar 

  28. Barbin A (2000) Etheno-adduct-forming chemicals: from mutagenicity testing to tumor mutation spectra. Mutat Res 462(2–3):55–69

    Article  CAS  Google Scholar 

  29. Bartsch H, Barbin A, Marion MJ et al (1994) Formation, detection, and role in carcinogenesis of ethenobases in DNA. Drug Metab Rev 26(1–2):349–371

    Article  CAS  Google Scholar 

  30. Basu AK, Wood ML, Niedernhofer LJ et al (1993) Mutagenic and genotoxic effects of three vinyl chloride-induced DNA lesions: 1,N6-ethenoadenine, 3,N4-ethenocytosine, and 4-amino-5-(imidazol-2-yl)imidazole. Biochemistry 32(47):12793–12801

    Article  CAS  Google Scholar 

  31. Pandya GA, Moriya M (1996) 1,N6-ethenodeoxyadenosine, a DNA adduct highly mutagenic in mammalian cells. Biochemistry 35(35):11487–11492

    Article  CAS  Google Scholar 

  32. Palejwala VA, Rzepka RW, Simha D et al (1993) Quantitative multiplex sequence analysis of mutational hot spots. Frequency and specificity of mutations induced by a site-specific ethenocytosine in M13 viral DNA. Biochemistry 32(15):4105–4111

    Article  CAS  Google Scholar 

  33. Moriya M, Zhang W, Johnson F et al (1994) Mutagenic potency of exocyclic DNA adducts: marked differences between Escherichia coli and simian kidney cells. Proc Natl Acad Sci U S A 91(25):11899–11903

    Article  CAS  Google Scholar 

  34. Levine RL, Yang IY, Hossain M et al (2000) Mutagenesis induced by a single 1,N6-ethenodeoxyadenosine adduct in human cells. Cancer Res 60(15):4098–4104

    CAS  PubMed  Google Scholar 

  35. Swenberg JA, Fedtke N et al (1992) Etheno adducts formed in DNA of vinyl chloride-exposed rats are highly persistent in liver. Carcinogenesis 13(4):727–729

    Article  CAS  Google Scholar 

  36. Cheng KC, Preston BD, Cahill DS et al (1991) The vinyl chloride DNA derivative N2,3-ethenoguanine produces G–A transitions in Escherichia coli. Proc Natl Acad Sci U S A 88(22):9974–9978

    Article  CAS  Google Scholar 

  37. Hu W, Feng Z, Eveleigh J et al (2002) The major lipid peroxidation product, trans-4-hydroxy-2-nonenal, preferentially forms DNA adducts at codon 249 of human p53 gene, a unique mutational hotspot in hepatocellular carcinoma. Carcinogenesis 23(11):1781–1789

    Article  CAS  Google Scholar 

  38. European Association for the Study of the Liver (2012) EASL clinical practical guidelines: management of alcoholic liver disease. J Hepatol 57(2):399–420

    Article  Google Scholar 

  39. Lieber CS (1999) Microsomal ethanol-oxidizing system (MEOS): the first 30 years (1968–1998)–a review. Alcohol Clin Exp Res 23(6):991–1007

    CAS  PubMed  Google Scholar 

  40. Weltman MD, Farrell GC, Hall P et al (1998) Hepatic cytochrome P450 2E1 is increased in patients with nonalcoholic steatohepatitis. Hepatology 27(1):128–133

    Article  CAS  Google Scholar 

  41. Oneta CM, Lieber CS, Li J et al (2002) Dynamics of cytochrome P4502E1 activity in man: induction by ethanol and disappearance during withdrawal phase. J Hepatol 36(1):47–52

    Article  CAS  Google Scholar 

  42. Lieber CS (2004) CYP2E1: from ASH to NASH. Hepatol Res 28(1):1–11

    Article  CAS  Google Scholar 

  43. Lu Y, Wu D, Wang X et al (2010) Chronic alcohol-induced liver injury and oxidant stress are decreased in cytochrome P4502E1 knockout mice and restored in humanized cytochrome P4502E1 knock-in mice. Free Radic Biol Med 49(9):1406–1416

    Article  CAS  Google Scholar 

  44. Lu Y, Zhuge J, Wang X et al (2008) Cytochrome P450 2E1 contributes to ethanol-induced fatty liver in mice. Hepatology 47(5):1483–1494

    Article  CAS  Google Scholar 

  45. Gouillon Z, Lucas D, Li J et al (2000) Inhibition of ethanol-induced liver disease in the intragastric feeding rat model by chlormethiazole. Proc Soc Exp Biol Med 224(4):302–308

    Article  CAS  Google Scholar 

  46. Bradford BU, Kono H, Isayama F et al (2005) Cytochrome P450 CYP2E1, but not nicotinamide adenine dinucleotide phosphate oxidase, is required for ethanol-induced oxidative DNA damage in rodent liver. Hepatology 41(2):336–344

    Article  CAS  Google Scholar 

  47. Morgan K, French SW, Morgan TR (2002) Production of a cytochrome P450 2E1 transgenic mouse and initial evaluation of alcoholic liver damage. Hepatology 36(1):122–134

    Article  CAS  Google Scholar 

  48. Butura A, Nilsson K, Morgan K et al (2009) The impact of CYP2E1 on the development of alcoholic liver disease as studied in a transgenic mouse model. J Hepatol 50(3):572–583

    Article  CAS  Google Scholar 

  49. Wang Y, Millonig G, Nair J et al (2009 Aug) Ethanol-induced cytochrome P4502E1 causes carcinogenic etheno-DNA lesions in alcoholic liver disease. Hepatology 50(2):453–461

    Article  CAS  Google Scholar 

  50. Millonig G, Wang Y, Homann N et al (2011) Ethanol-mediated carcinogenesis in the human esophagus implicates CYP2E1 induction and the generation of carcinogenic DNA-lesions. Int J Cancer 128(3):533–540

    Article  CAS  Google Scholar 

  51. Köhler BC, Arslic-Schmitt T, Pecerella T et al (2016) Possible mechanisms of ethanol mediated colorectal carcinogenesis: the role of cytochrome P4502E1, etheno-DNA adducts and the anti-apoptotic protein Mcl-1. Alcohol Clin Exp Res 40(10):2094–2101

    Article  CAS  Google Scholar 

  52. Chalasani N, Gorski JC et al (2003) Hepatic cytochrome P450 2E1 activity in nondiabetic patients with nonalcoholic steatohepatitis. Hepatology 37(3):544–50.r

    Article  CAS  Google Scholar 

  53. Teufel U, Peccerella T, Engelmann G et al (2015) Detection of carcinogenic etheno-DNA adducts in children and adolescents with non-alcoholic steatohepatitis (NASH). Hepatobiliary Surg Nutr 4(6):426–435

    PubMed  PubMed Central  Google Scholar 

  54. Wang Y, Seitz H, Wang X (2010) Moderate alcohol consumption aggravates high-fat diet induced steatohepatitis in rats. Alcohol Clin Exp Res 34(3):567–573

    Article  CAS  Google Scholar 

  55. Duly AM, Alani B, Huang EY et al (2015) Effect of multiple binge alcohol on diet-induced liver injury in a mouse model of obesity. Nutr Diabetes 5:e154

    Article  CAS  Google Scholar 

  56. Seth D, Hogg PJ, Gorrell MD et al (2008) Direct effects of alcohol on hepatic fibrinolytic balance: implications for alcoholic liver disease. J Hepatol 48(4):614–627

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Centre of Alcohol Research (CAR), University of Heidelberg, Heidelberg, Germany

    Teresa Peccerella, Sebastian Mueller & Helmut K. Seitz

  2. Department of Medicine, Salem Medical Centre, Heidelberg, Germany

    Tatjana Arslic-Schmitt, Sebastian Mueller, Kirstin-Berit Linhart & Helmut K. Seitz

  3. Drug Health Services, Royal Prince Alfred Hospital, and Centenary Institute of Cancer Medicine and Cell Biology, Camperdown, Australia; Central Clinical School, University of Sydney, Sydney, NSW, Australia

    Devanshi Seth

  4. Erstwhile: Division of Toxicology and Cancer Risk Factors, German Cancer Research Centre (DKFZ), Heidelberg, Germany

    Helmut Bartsch

Authors
  1. Teresa Peccerella
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tatjana Arslic-Schmitt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sebastian Mueller
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kirstin-Berit Linhart
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Devanshi Seth
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Helmut Bartsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Helmut K. Seitz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Helmut K. Seitz .

Editor information

Editors and Affiliations

  1. Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA

    Vasilis Vasiliou

  2. Distilled Spirits Council of the US, Washington, DC, USA

    Samir Zakhari

  3. Mishra Laboratory, University of Texas, MD Anderson Cancer Center, Houston, TX, USA

    Lopa Mishra

  4. Salem Medical Centre, University of Heidelberg, Heidelberg, Baden-Württemberg, Germany

    Helmut K. Seitz

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Nature Switzerland AG

About this paper

Check for updates. Verify currency and authenticity via CrossMark

Cite this paper

Peccerella, T. et al. (2018). Chronic Ethanol Consumption and Generation of Etheno-DNA Adducts in Cancer-Prone Tissues. In: Vasiliou, V., Zakhari, S., Mishra, L., Seitz, H. (eds) Alcohol and Cancer. Advances in Experimental Medicine and Biology, vol 1032. Springer, Cham. https://doi.org/10.1007/978-3-319-98788-0_6

Download citation

Publish with us

Policies and ethics

Search

Navigation