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PMID: 12077107 Published · ppublish English Journal Article Review

Cocarcinogenic effects of alcohol in hepatocarcinogenesis.

Gut ·Vol. 51 ·No. 1 ·2002-07-00 ·Pages 132-9

Stickel F, Schuppan D, Hahn EG, Seitz HK

Abstract

Alcohol is a major aetiological factor in hepatocarcinogenesis but our understanding of its importance as a modulating factor is just beginning to emerge. In the present review, a number of possible cofactors and mechanisms are discussed by which alcohol may enhance the development of hepatoma. These include dietary or environmental carcinogens ingested along with alcoholic beverages, alcoholic cirrhosis as a precancerous condition, and the effects of alcohol metabolism.

MeSH Terms
Acetaldehyde/adverse effects,metabolism Animals Carcinogens Carcinoma, Hepatocellular/chemically induced,etiology,immunology Cocarcinogenesis Cytokines/immunology Diet/adverse effects Environmental Pollutants/adverse effects Ethanol/adverse effects,metabolism Hepatitis/complications Humans Immune Tolerance Liver/metabolism Liver Cirrhosis, Alcoholic/complications Liver Neoplasms/chemically induced,etiology,immunology Precancerous Conditions Retinoids/metabolism
Chemicals
Carcinogens Cytokines Environmental Pollutants Retinoids Ethanol Acetaldehyde
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Stickel F
Department of Medicine I, Division of Hepatology, University of Erlangen-Nuremberg, Germany. felix.stickel@med.uni-erlangen.de
Schuppan D
Hahn E G
Seitz H K
References (104)
104 references, click to expand
  1. Hepatic vitamin A depletion in alcoholic liver injury.
    N Engl J Med. 1982 Sep 2;307(10):597-601 PMID: 7202119
  2. Effect of chronic alcohol consumption on tumor incidence due to dimethylnitrosamine administration.
    J Cancer Res Clin Oncol. 1983;106(1):58-64 PMID: 6684119
  3. Increased loss and decreased synthesis of hepatic glutathione after acute ethanol administration. Turnover studies.
    Biochem J. 1985 Feb 1;225(3):565-72 PMID: 3977847
  4. Is mallory body formation a preneoplastic change? A study of 181 cases of liver bearing hepatocellular carcinoma and 82 cases of cirrhosis.
    Cancer. 1985 May 15;55(10):2400-4 PMID: 2985233
  5. Immunochemical evidence for induction of the alcohol-oxidizing cytochrome P-450 of rabbit liver microsomes by diverse agents: ethanol, imidazole, trichloroethylene, acetone, pyrazole, and isoniazid.
    Proc Natl Acad Sci U S A. 1985 Jun;82(12):4065-9 PMID: 3858864
  6. Chronic alcoholism enhances hepatocarcinogenicity of diethylnitrosamine in rats fed a marginally methyl-deficient diet.
    Hepatology. 1985 Nov-Dec;5(6):1120-5 PMID: 4065819
  7. Acetaldehyde.
    IARC Monogr Eval Carcinog Risk Chem Hum. 1985 Feb;36:101-32 PMID: 2415444
  8. Effects of ethanol on experimental hepatocarcinogenesis.
    Hepatology. 1986 Jan-Feb;6(1):65-72 PMID: 2867966
  9. Dose-response relationships for initiation of rat liver tumours by diethylnitrosamine and promotion by phenobarbitone or alcohol.
    Food Chem Toxicol. 1986 Mar;24(3):241-5 PMID: 3957177
  10. Hepatitis C virus infection in alcoholic liver cirrhosis in Japan: its contribution to the development of hepatocellular carcinoma.
    Alcohol Alcohol Suppl. 1993;1A:85-90 PMID: 8141927
  11. Alcohol and the liver: 1994 update.
    Gastroenterology. 1994 Apr;106(4):1085-105 PMID: 8143977
  12. Increased serum hepatitis C virus RNA levels among alcoholic patients with chronic hepatitis C.
    Hepatology. 1994 Nov;20(5):1115-20 PMID: 7523270
  13. Effects of ethanol consumption on enriched natural killer cells from C57BL/6 mice.
    Alcohol Clin Exp Res. 1994 Jun;18(3):625-31 PMID: 7943666
  14. Ethanol decreases the number and activity of splenic natural killer cells in a mouse model for binge drinking.
    J Pharmacol Exp Ther. 1994 Nov;271(2):722-9 PMID: 7965788
  15. Breaks in genomic DNA and within the p53 gene are associated with hypomethylation in livers of folate/methyl-deficient rats.
    Cancer Res. 1995 May 1;55(9):1894-901 PMID: 7794383
  16. Experimental liver cirrhosis induced by alcohol and iron.
    J Clin Invest. 1995 Jul;96(1):620-30 PMID: 7615836
  17. Alterations in DNA methylation may play a variety of roles in carcinogenesis.
    Cell. 1995 Oct 6;83(1):13-5 PMID: 7553865
  18. Development of a 32P-postlabelling method for the analysis of adducts arising through the reaction of acetaldehyde with 2'-deoxyguanosine-3'-monophosphate and DNA.
    Carcinogenesis. 1995 Sep;16(9):2177-85 PMID: 7554072
  19. Cytochrome P450 2E1 and glutathione S-transferase M1 polymorphisms and susceptibility to hepatocellular carcinoma.
    Gastroenterology. 1995 Oct;109(4):1266-73 PMID: 7557094
  20. Appearance of oval cells in the liver of rats after long-term exposure to ethanol.
    Hepatology. 1996 Jan;23(1):145-54 PMID: 8550034
  21. Role of cytochrome P4502E1-dependent formation of hydroxyethyl free radical in the development of liver damage in rats intragastrically fed with ethanol.
    Hepatology. 1996 Jan;23(1):155-63 PMID: 8550035
  22. Acute alcohol intoxication suppresses natural killer cell activity and promotes tumor metastasis.
    Nat Med. 1996 Apr;2(4):457-60 PMID: 8597957
  23. Copper-dependent formation of miscoding etheno-DNA adducts in the liver of Long Evans cinnamon (LEC) rats developing hereditary hepatitis and hepatocellular carcinoma.
    Cancer Res. 1996 Mar 15;56(6):1267-71 PMID: 8640812
  24. Hepatic iron contents and response to interferon-alpha in patients with chronic hepatitis C. Relationship to genotypes of hepatitis C virus.
    Dig Dis Sci. 1996 May;41(5):989-94 PMID: 8625774
  25. A decade of molecular biology of retinoic acid receptors.
    FASEB J. 1996 Jul;10(9):940-54 PMID: 8801176
  26. Hepatitis C virus infection as a major risk factor for hepatocellular carcinoma.
    J Hepatol. 1996;24(2 Suppl):61-6 PMID: 8836891
  27. Effect of alcohol drinking on gene expression of hepatic O6-methylguanine DNA methyltransferase in chronic liver diseases.
    Alcohol Clin Exp Res. 1996 Dec;20(9 Suppl):297A-300A PMID: 8986226
  28. Chronic hepatitis C: effect of alcohol on hepatitic activity and viral titre.
    J Hepatol. 1996 Dec;25(6):821-6 PMID: 9007708
  29. Initiation of liver growth by tumor necrosis factor: deficient liver regeneration in mice lacking type I tumor necrosis factor receptor.
    Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1441-6 PMID: 9037072
  30. Nutritional deficiencies in chronic alcoholics: relation to dietary intake and alcohol consumption.
    Am J Gastroenterol. 1997 Mar;92(3):485-9 PMID: 9068475
  31. Treatment of hepatocellular carcinoma: a systematic review of randomized controlled trials.
    Ann Oncol. 1997 Feb;8(2):117-36 PMID: 9093719
  32. Decreased natural killer cytotoxic activity in chronic alcoholism is associated with alcohol liver disease but not active ethanol consumption.
    Hepatology. 1997 May;25(5):1096-100 PMID: 9141423
  33. Lack of association of cytochrome P450 2E1 genetic polymorphisms with the risk of human hepatocellular carcinoma.
    Int J Cancer. 1997 May 29;71(5):737-40 PMID: 9180139
  34. Chlormethiazole inhibition of cytochrome P450 2E1 as assessed by chlorzoxazone hydroxylation in humans.
    Hepatology. 1997 Oct;26(4):957-61 PMID: 9328319
  35. Increase in primary liver cancer in the UK, 1979-94.
    Lancet. 1997 Oct 18;350(9085):1142-3 PMID: 9343506
  36. Effect of alcohol consumption on serum hepatitis C virus RNA and histological lesions in chronic hepatitis C.
    Hepatology. 1998 Jun;27(6):1717-22 PMID: 9620348
  37. Chronic alcohol intake reduces retinoic acid concentration and enhances AP-1 (c-Jun and c-Fos) expression in rat liver.
    Hepatology. 1998 Sep;28(3):744-50 PMID: 9731567
  38. Correlation between DNA methylation and pathological changes in human hepatocellular carcinoma.
    Hepatogastroenterology. 1998 Sep-Oct;45(23):1753-9 PMID: 9840141
  39. Alcohol abuse, alcoholism, and damage to the immune system--a review.
    Alcohol Clin Exp Res. 1998 Dec;22(9):1927-42 PMID: 9884135
  40. Hepatocellular carcinoma in alcoholic liver disease: no evidence for a pathogenetic role of hepatitis B virus infection.
    Hepatology. 1988 Jul-Aug;8(4):745-8 PMID: 2839403
  41. Oval cell numbers in human chronic liver diseases are directly related to disease severity.
    Am J Pathol. 1999 Feb;154(2):537-41 PMID: 10027411
  42. DNA hypermethylation at the D17S5 locus and reduced HIC-1 mRNA expression are associated with hepatocarcinogenesis.
    Hepatology. 1999 Mar;29(3):703-9 PMID: 10051471
  43. DNA methylation is a reversible biological signal.
    Proc Natl Acad Sci U S A. 1999 May 25;96(11):6107-12 PMID: 10339549
  44. Alcohol, vitamin A, and beta-carotene: adverse interactions, including hepatotoxicity and carcinogenicity.
    Am J Clin Nutr. 1999 Jun;69(6):1071-85 PMID: 10357725
  45. Chronic alcohol consumption induces genomic but not p53-specific DNA hypomethylation in rat colon.
    J Nutr. 1999 Nov;129(11):1945-50 PMID: 10539767
  46. Hepatitis C and alcohol.
    J Hepatol. 1999;31 Suppl 1:113-8 PMID: 10622572
  47. Consequences of alcohol consumption on host defence.
    Alcohol Alcohol. 1999 Nov-Dec;34(6):830-41 PMID: 10659718
  48. Aberrant DNA methylation precedes loss of heterozygosity on chromosome 16 in chronic hepatitis and liver cirrhosis.
    Cancer Lett. 2000 Jan 1;148(1):73-80 PMID: 10680595
  49. S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial.
    J Hepatol. 1999 Jun;30(6):1081-9 PMID: 10406187
  50. Molecular basis of multistep hepatocarcinogenesis: genetic and epigenetic events.
    Scand J Gastroenterol. 1999 Aug;34(8):737-42 PMID: 10499472
  51. Effects of transforming growth factor beta on the functions of natural killer cells: depressed cytolytic activity and blunting of interferon responsiveness.
    J Immunol. 1986 May 15;136(10):3916-20 PMID: 2871107
  52. Anemia in alcoholics.
    Medicine (Baltimore). 1986 Sep;65(5):322-38 PMID: 3747828
  53. The effects of chronic ethanol consumption on carcinogen metabolism and on O6-methylguanine transferase-mediated repair of alkylated DNA.
    Alcohol Clin Exp Res. 1986;10(6 Suppl):73S-77S PMID: 3544934
  54. Catalytic properties of human liver alcohol dehydrogenase isoenzymes.
    Enzyme. 1987;37(1-2):19-28 PMID: 3569190
  55. Functional analysis of T-cell subsets in chronic experimental alcoholism.
    Immunology. 1987 May;61(1):63-9 PMID: 2953674
  56. Influence of ethyl alcohol on carcinogenesis induced by volatile N-nitrosamines detected in alcoholic beverages.
    IARC Sci Publ. 1987;(84):264-5 PMID: 3679382
  57. Long-term cancer risk in alcoholism.
    Alcohol Alcohol. 1988;23(2):163-71 PMID: 3390240
  58. The c-Fos protein interacts with c-Jun/AP-1 to stimulate transcription of AP-1 responsive genes.
    Cell. 1988 Aug 12;54(4):541-52 PMID: 3135940
  59. Enhanced demethylation and denitrosation of N-nitrosodimethylamine by human liver microsomes from alcoholics.
    Cancer Lett. 1989 Jul 1;46(1):43-9 PMID: 2736507
  60. Rapid appearance of hypomethylated DNA in livers of rats fed cancer-promoting, methyl-deficient diets.
    Cancer Res. 1989 Aug 1;49(15):4094-7 PMID: 2743304
  61. HBV-DNA hybridization in hepatocellular carcinoma associated with alcohol in Japan.
    J Med Virol. 1989 Jul;28(3):189-92 PMID: 2547022
  62. Experimental methods of ethanol administration.
    Hepatology. 1989 Oct;10(4):501-10 PMID: 2673971
  63. S-adenosyl-L-methionine attenuates alcohol-induced liver injury in the baboon.
    Hepatology. 1990 Feb;11(2):165-72 PMID: 2307395
  64. Prospective study of early detection of hepatocellular carcinoma in patients with cirrhosis.
    Hepatology. 1990 Oct;12(4 Pt 1):680-7 PMID: 1698703
  65. Circulating tumor necrosis factor, interleukin-1 and interleukin-6 concentrations in chronic alcoholic patients.
    Hepatology. 1991 Feb;13(2):267-76 PMID: 1995437
  66. Ethanol consumption inhibits fetal DNA methylation in mice: implications for the fetal alcohol syndrome.
    Alcohol Clin Exp Res. 1991 Jun;15(3):395-8 PMID: 1877725
  67. Activated CD-8 cells and HLA DR expression in alcoholics without overt liver disease.
    J Clin Immunol. 1991 Sep;11(5):246-53 PMID: 1839029
  68. Methyl groups in carcinogenesis: effects on DNA methylation and gene expression.
    Cancer Res. 1992 Apr 1;52(7 Suppl):2071s-2077s PMID: 1544143
  69. The onset of oncogene hypomethylation in the livers of rats fed methyl-deficient, amino acid-defined diets.
    Carcinogenesis. 1992 Oct;13(10):1869-72 PMID: 1330345
  70. Interaction between alcohol consumption and positivity for antibodies to hepatitis C virus on the risk of liver cirrhosis: a case-control study. Provincial Group for the Study of Chronic Liver Disease.
    Eur J Epidemiol. 1992 Sep;8(5):634-9 PMID: 1330673
  71. Prevalence of hepatocellular carcinoma in patients with alcoholic cirrhosis and prior exposure to hepatitis C.
    Am J Gastroenterol. 1993 Jan;88(1):39-43 PMID: 7678368
  72. Reversibility of changes in nucleic acid methylation and gene expression induced in rat liver by severe dietary methyl deficiency.
    Carcinogenesis. 1993 Apr;14(4):551-7 PMID: 8472313
  73. Alcohol and aldehyde dehydrogenase polymorphisms and alcoholism.
    Behav Genet. 1993 Mar;23(2):131-6 PMID: 8512527
  74. Circulating and tissue levels of the neutrophil chemotaxin interleukin-8 are elevated in severe acute alcoholic hepatitis, and tissue levels correlate with neutrophil infiltration.
    Hepatology. 1993 Jul;18(1):41-6 PMID: 8325620
  75. Aflatoxin B1 induces the transversion of G-->T in codon 249 of the p53 tumor suppressor gene in human hepatocytes.
    Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8586-90 PMID: 8397412
  76. The effect of ethanol on one-carbon metabolism: increased methionine catabolism and lipotrope methyl-group wastage.
    Hepatology. 1993 Oct;18(4):984-9 PMID: 7691709
  77. Genomic abnormalities in hepatocarcinogenesis. Implications for a chemopreventive strategy.
    Anticancer Res. 1993 Sep-Oct;13(5A):1341-56 PMID: 8239505
  78. Role of ethanol-inducible cytochrome P-450 2E1 in the development of hepatocellular carcinoma by the chemical carcinogen, N-nitrosodimethylamine.
    Hepatology. 1993 Dec;18(6):1483-9 PMID: 8244274
  79. The relationship of ethanol feeding to the methyl folate trap.
    Alcohol. 1993 Nov-Dec;10(6):495-7 PMID: 8123207
  80. Tobacco smoking, alcohol consumption and their interaction in the causation of hepatocellular carcinoma.
    Int J Cancer. 2000 Feb 15;85(4):498-502 PMID: 10699921
  81. Genetic polymorphism of alcohol dehydrogenase in europeans: the ADH2*2 allele decreases the risk for alcoholism and is associated with ADH3*1.
    Hepatology. 2000 Apr;31(4):984-9 PMID: 10733556
  82. Relationship between alcohol drinking, ADH2 and ALDH2 genotypes, and risk for hepatocellular carcinoma in Japanese.
    Cancer Lett. 2000 Feb 28;149(1-2):69-76 PMID: 10737710
  83. Effect of chronic alcohol consumption on total plasma homocysteine level in rats.
    Alcohol Clin Exp Res. 2000 Mar;24(3):259-64 PMID: 10776661
  84. Contribution of hepatitis C virus to the progression of alcoholic liver disease.
    Alcohol Clin Exp Res. 2000 Apr;24(4 Suppl):112S-116S PMID: 10803792
  85. Genetic polymorphisms of cytochrome p4502E1 and susceptibility to alcoholic liver disease and hepatocellular carcinoma in a white population: a study and literature review, including meta-analysis.
    Mol Pathol. 2000 Apr;53(2):88-93 PMID: 10889908
  86. Inhibition of ethanol-induced liver disease in the intragastric feeding rat model by chlormethiazole.
    Proc Soc Exp Biol Med. 2000 Sep;224(4):302-8 PMID: 10964266
  87. Genetic instability and aberrant DNA methylation in chronic hepatitis and cirrhosis--A comprehensive study of loss of heterozygosity and microsatellite instability at 39 loci and DNA hypermethylation on 8 CpG islands in microdissected specimens from patients with hepatocellular carcinoma.
    Hepatology. 2000 Nov;32(5):970-9 PMID: 11050047
  88. Cytokines in alcoholic and nonalcoholic steatohepatitis.
    N Engl J Med. 2000 Nov 16;343(20):1467-76 PMID: 11078773
  89. Alcohol and retinoid metabolism.
    Gut. 2000 Dec;47(6):748-50 PMID: 11076870
  90. Frequent hypermethylation of CpG islands and loss of expression of the 14-3-3 sigma gene in human hepatocellular carcinoma.
    Oncogene. 2000 Nov 2;19(46):5298-302 PMID: 11077447
  91. Risk factors for the rising rates of primary liver cancer in the United States.
    Arch Intern Med. 2000 Nov 27;160(21):3227-30 PMID: 11088082
  92. Ethanol enhances retinoic acid metabolism into polar metabolites in rat liver via induction of cytochrome P4502E1.
    Gastroenterology. 2001 Jan;120(1):179-89 PMID: 11208727
  93. Endotoxin, endotoxin-neutralizing-capacity, sCD14, sICAM-1, and cytokines in patients with various degrees of alcoholic liver disease.
    Alcohol Clin Exp Res. 2001 Feb;25(2):261-8 PMID: 11236841
  94. Viruses and alcohol in the pathogenesis of primary hepatic carcinoma.
    Eur J Cancer Prev. 2001 Feb;10(1):107-10 PMID: 11263585
  95. Restoration of retinoic acid concentration suppresses ethanol-enhanced c-Jun expression and hepatocyte proliferation in rat liver.
    Carcinogenesis. 2001 Aug;22(8):1213-9 PMID: 11470752
  96. Serum collagen type VI and XIV and hyaluronic acid as early indicators for altered connective tissue turnover in alcoholic liver disease.
    Dig Dis Sci. 2001 Sep;46(9):2025-32 PMID: 11575459
  97. Vitamin B6 metabolism in chronic alcohol abuse. Pyridoxal phosphate levels in plasma and the effects of acetaldehyde on pyridoxal phosphate synthesis and degradation in human erythrocytes.
    J Clin Invest. 1974 Mar;53(3):693-704 PMID: 4359937
  98. Vitamin B6 deficiency in chronic liver disease--evidence for increased degradation of pyridoxal-5'-phosphate.
    Gut. 1977 Jan;18(1):23-7 PMID: 838399
  99. Early histological and functional alterations of ethionine liver carcinogenesis in rats fed a choline-deficient diet.
    Cancer Res. 1978 Apr;38(4):1092-8 PMID: 76508
  100. Mutagenic, cancerogenic and teratogenic effects of alcohol.
    Mutat Res. 1979 Dec;65(4):229-59 PMID: 117354
  101. Enhancement of dimethylnitrosamine metabolism and activation to a mutagen following chronic ethanol consumption.
    Cancer Res. 1981 Jan;41(1):120-4 PMID: 7192597
  102. Primary hepatic cancer in alcoholics.
    Clin Gastroenterol. 1981 May;10(2):457-77 PMID: 6265122
  103. Evidence that hepatitis B virus has a role in liver-cell carcinoma in alcoholic liver disease.
    N Engl J Med. 1982 Jun 10;306(23):1384-7 PMID: 6281640
  104. A case-control dietary study of primary liver cancer risk from aflatoxin exposure.
    Int J Epidemiol. 1982 Jun;11(2):112-9 PMID: 7095960
Article Info
Journal
Gut
Abbr.
Gut
ISSN
0017-5749
DOI
10.1136/gut.51.1.132
Email
felix.stickel@med.uni-erlangen.de
Published
2002-07-00
Pages
132-9
Language
English
Region
England
NLM ID
2985108R
PMCID
PMC1773267
Subset
IM
External Links
PubMed source DOI: 10.1136/gut.51.1.132 PMC Full Text View journal details
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