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Semin Liver Dis 2009; 29(2): 222-232
DOI: 10.1055/s-0029-1214377
© Thieme Medical Publishers

Role of Alcohol in Liver Carcinogenesis

Iain H. McKillop1 , Laura W. Schrum2
  • 1Department of General Surgery, Carolinas Medical Center, Charlotte, North Carolina
  • 2Department of Biology, University of North Carolina at Charlotte, Charlotte, North Carolina
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Publikationsverlauf

Publikationsdatum:
22. April 2009 (online)

    Lizenzen und Reprints

ABSTRACT

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world and contributes significantly to cancer-related morbidity and mortality. Chronic alcohol consumption has long been associated with progressive liver disease toward the development of hepatic cirrhosis and the subsequent increased risk for developing HCC. In assessing the role of alcohol during hepatic disease, and as a carcinogen, many of the deleterious effects of alcohol can be attributed to alcohol metabolism in hepatocytes. In addition to the direct effects of alcohol/alcohol metabolism on hepatocyte transformation, increasing evidence indicates that other intrahepatic and systemic effects of alcohol are likely to play an equally significant role in the process of hepatic tumorigenesis.

KEYWORDS

Alcohol - acetaldehyde - hepatocellular carcinoma - carcinogenesis - metabolism

REFERENCES

  • 1 McKillop I H, Moran D M, Jin X, Koniaris L G. Molecular pathogenesis of hepatocellular carcinoma.  J Surg Res. 2006;  136(1) 125-135
    CrossrefPubMedGoogle Scholar
  • 2 Parkin D M. Global cancer statistics in the year 2000.  Lancet Oncol. 2001;  2(9) 533-543
    CrossrefPubMedGoogle Scholar
  • 3 Shibuya K, Mathers C D, Boschi-Pinto C, Lopez A D, Murray C J. Global and regional estimates of cancer mortality and incidence by site: II. Results for the global burden of disease 2000.  BMC Cancer. 2002;  2 37
    CrossrefPubMedGoogle Scholar
  • 4 McGlynn K A, London W T. Epidemiology and natural history of hepatocellular carcinoma.  Best Pract Res Clin Gastroenterol. 2005;  19(1) 3-23
    CrossrefPubMedGoogle Scholar
  • 5 McGlynn K A, Tsao L, Hsing A W, Devesa S S, Fraumeni Jr J F. International trends and patterns of primary liver cancer.  Int J Cancer. 2001;  94(2) 290-296
    CrossrefPubMedGoogle Scholar
  • 6 Marrero J A. Hepatocellular carcinoma.  Curr Opin Gastroenterol. 2005;  21(3) 308-312
    CrossrefPubMedGoogle Scholar
  • 7 Okuda K. Hepatocellular carcinoma.  J Hepatol. 2000;  32(suppl) 225-237
    PubMedGoogle Scholar
  • 8 Pang R W, Joh J W, Johnson P J et al.. Biology of hepatocellular carcinoma.  Ann Surg Oncol. 2008;  15(4) 962-971
    CrossrefPubMedGoogle Scholar
  • 9 El-Serag H B, Mason A C. Risk factors for the rising rates of primary liver cancer in the United States.  Arch Intern Med. 2000;  160(21) 3227-3230
    CrossrefPubMedGoogle Scholar
  • 10 El-Serag H B, Rudolph K L. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis.  Gastroenterology. 2007;  132(7) 2557-2576
    CrossrefPubMedGoogle Scholar
  • 11 Moradpour D, Blum H E. Pathogenesis of hepatocellular carcinoma.  Eur J Gastroenterol Hepatol. 2005;  17(5) 477-483
    CrossrefPubMedGoogle Scholar
  • 12 Farazi P A, DePinho R A. The genetic and environmental basis of hepatocellular carcinoma.  Discov Med. 2006;  6(35) 182-186
    PubMedGoogle Scholar
  • 13 Kew M C. Synergistic interaction between aflatoxin B1 and hepatitis B virus in hepatocarcinogenesis.  Liver Int. 2003;  23(6) 405-409
    CrossrefPubMedGoogle Scholar
  • 14 Pang R, Tse E, Poon R T. Molecular pathways in hepatocellular carcinoma.  Cancer Lett. 2006;  240(2) 157-169
    CrossrefPubMedGoogle Scholar
  • 15 Poon R T. Optimal initial treatment for early hepatocellular carcinoma in patients with preserved liver function: transplantation or resection?.  Ann Surg Oncol. 2007;  14(2) 541-547
    CrossrefPubMedGoogle Scholar
  • 16 Yu M C, Yuan J M. Environmental factors and risk for hepatocellular carcinoma.  Gastroenterology. 2004;  127(suppl 1) S72-S78
    CrossrefPubMedGoogle Scholar
  • 17 El-Serag H B, Mason A C. Rising incidence of hepatocellular carcinoma in the United States.  N Engl J Med. 1999;  340(10) 745-750
    CrossrefPubMedGoogle Scholar
  • 18 McKillop I H, Schrum L W. Alcohol and liver cancer.  Alcohol. 2005;  35(3) 195-203
    CrossrefPubMedGoogle Scholar
  • 19 Taylor-Robinson S D, Foster G R, Arora S, Hargreaves S, Thomas H C. Increase in primary liver cancer in the UK, 1979–94.  Lancet. 1997;  350(9085) 1142-1143
    PubMedGoogle Scholar
  • 20 Voigt M D. Alcohol in hepatocellular cancer.  Clin Liver Dis. 2005;  9(1) 151-169
    CrossrefPubMedGoogle Scholar
  • 21 El-Serag H B, Marrero J A, Rudolph L, Reddy K R. Diagnosis and treatment of hepatocellular carcinoma.  Gastroenterology. 2008;  134(6) 1752-1763
    CrossrefPubMedGoogle Scholar
  • 22 Raoul J L. Natural history of hepatocellular carcinoma and current treatment options.  Semin Nucl Med. 2008;  38(2) S13-S18
    CrossrefPubMedGoogle Scholar
  • 23 Crocetti L, Lencioni R. Thermal ablation of hepatocellular carcinoma.  Cancer Imaging. 2008;  8 19-26
    CrossrefPubMedGoogle Scholar
  • 24 Iannitti D A, Dupuy D E, Mayo-Smith W W, Murphy B. Hepatic radiofrequency ablation.  Arch Surg. 2002;  137(4) 422-426 discussion 427
    PubMedGoogle Scholar
  • 25 Ishizaki Y, Kawasaki S. The evolution of liver transplantation for hepatocellular carcinoma (past, present, and future).  J Gastroenterol. 2008;  43(1) 18-26
    CrossrefPubMedGoogle Scholar
  • 26 Masaki T, Morishita A, Kurokohchi K, Kuriyama S. Multidisciplinary treatment of patients with hepatocellular carcinoma.  Expert Rev Anticancer Ther. 2006;  6(10) 1377-1384
    CrossrefPubMedGoogle Scholar
  • 27 Mazzaferro V, Chun Y S, Poon R T et al.. Liver transplantation for hepatocellular carcinoma.  Ann Surg Oncol. 2008;  15(4) 1001-1007
    CrossrefPubMedGoogle Scholar
  • 28 Yamazaki S, Takayama T. Surgical treatment of hepatocellular carcinoma: evidence-based outcomes.  World J Gastroenterol. 2008;  14(5) 685-692
    CrossrefPubMedGoogle Scholar
  • 29 Abdalla E K, Denys A, Hasegawa K et al.. Treatment of large and advanced hepatocellular carcinoma.  Ann Surg Oncol. 2008;  15(4) 979-985
    CrossrefPubMedGoogle Scholar
  • 30 Forner A, Hessheimer A J, Isabel Real M, Bruix J. Treatment of hepatocellular carcinoma.  Crit Rev Oncol Hematol. 2006;  60(2) 89-98
    CrossrefPubMedGoogle Scholar
  • 31 Francoz C, Durand F. The risk of surgery in patients with cirrhosis.  Acta Gastroenterol Belg. 2008;  71(1) 42-46 discussion 47
    PubMedGoogle Scholar
  • 32 Zimmerman M A, Ghobrial R M, Tong M J et al.. Recurrence of hepatocellular carcinoma following liver transplantation: a review of preoperative and postoperative prognostic indicators.  Arch Surg. 2008;  143(2) 182-188 discussion 188
    PubMedGoogle Scholar
  • 33 Gemma S, Vichi S, Testai E. Individual susceptibility and alcohol effects: biochemical and genetic aspects.  Ann Ist Super Sanita. 2006;  42(1) 8-16
    PubMedGoogle Scholar
  • 34 Norberg A, Jones A W, Hahn R G, Gabrielsson J L. Role of variability in explaining ethanol pharmacokinetics: research and forensic applications.  Clin Pharmacokinet. 2003;  42(1) 1-31
    CrossrefPubMedGoogle Scholar
  • 35 Crabb D W, Liangpunsakul S. Acetaldehyde generating enzyme systems: roles of alcohol dehydrogenase, CYP2E1 and catalase, and speculations on the role of other enzymes and processes.  Novartis Found Symp. 2007;  285 4-16 discussion 16-22
    PubMedGoogle Scholar
  • 36 Eriksson C J. The role of acetaldehyde in the actions of alcohol (update 2000).  Alcohol Clin Exp Res. 2001;  25(suppl) 15S-32S
    PubMedGoogle Scholar
  • 37 Seitz H K, Becker P. Alcohol metabolism and cancer risk.  Alcohol Res Health. 2007;  30(1) 38-41
    PubMedGoogle Scholar
  • 38 Tuma D J, Casey C A. Dangerous byproducts of alcohol breakdown–focus on adducts.  Alcohol Res Health. 2003;  27(4) 285-290
    PubMedGoogle Scholar
  • 39 Zakhari S. Overview: how is alcohol metabolized by the body?.  Alcohol Res Health. 2006;  29(4) 245-254
    PubMedGoogle Scholar
  • 40 Bjorkhem I. On the role of alcohol dehydrogenase in omega-oxidation of fatty acids.  Eur J Biochem. 1972;  30(3) 441-451
    CrossrefPubMedGoogle Scholar
  • 41 Lieber C S. ALCOHOL: its metabolism and interaction with nutrients.  Annu Rev Nutr. 2000;  20 395-430
    CrossrefPubMedGoogle Scholar
  • 42 Deitrich R A, Petersen D, Vasiliou V. Removal of acetaldehyde from the body.  Novartis Found Symp. 2007;  285 23-40 discussion 40-51
    PubMedGoogle Scholar
  • 43 Jornvall H, Hoog J O. Nomenclature of alcohol dehydrogenases.  Alcohol Alcohol. 1995;  30(2) 153-161
    PubMedGoogle Scholar
  • 44 Ding J, Li S, Wu J et al.. Alcohol dehydrogenase-2 and aldehyde dehydrogenase-2 genotypes, alcohol drinking and the risk of primary hepatocellular carcinoma in a Chinese population.  Asian Pac J Cancer Prev. 2008;  9(1) 31-35
    PubMedGoogle Scholar
  • 45 Smith M. Genetics of human alcohol and aldehyde dehydrogenases.  Adv Hum Genet. 1986;  15 249-290
    PubMedGoogle Scholar
  • 46 Eng M Y, Luczak S E, Wall T L. ALDH2, ADH1B, and ADH1C genotypes in Asians: a literature review.  Alcohol Res Health. 2007;  30(1) 22-27
    PubMedGoogle Scholar
  • 47 Day C P. Genes or environment to determine alcoholic liver disease and non-alcoholic fatty liver disease.  Liver Int. 2006;  26(9) 1021-1028
    CrossrefPubMedGoogle Scholar
  • 48 Edenberg H J. The genetics of alcohol metabolism: role of alcohol dehydrogenase and aldehyde dehydrogenase variants.  Alcohol Res Health. 2007;  30(1) 5-13
    PubMedGoogle Scholar
  • 49 Monzoni A, Masutti F, Saccoccio G et al.. Genetic determinants of ethanol-induced liver damage.  Mol Med. 2001;  7(4) 255-262
    PubMedGoogle Scholar
  • 50 Homann N, Stickel F, Konig I R et al.. Alcohol dehydrogenase 1C*1 allele is a genetic marker for alcohol-associated cancer in heavy drinkers.  Int J Cancer. 2006;  118(8) 1998-2002
    CrossrefPubMedGoogle Scholar
  • 51 Cederbaum A I. CYP2E1–biochemical and toxicological aspects and role in alcohol-induced liver injury.  Mt Sinai J Med. 2006;  73(4) 657-672
    PubMedGoogle Scholar
  • 52 Das S K, Vasudevan D M. Alcohol-induced oxidative stress.  Life Sci. 2007;  81(3) 177-187
    CrossrefPubMedGoogle Scholar
  • 53 Konishi M, Ishii H. Role of microsomal enzymes in development of alcoholic liver diseases.  J Gastroenterol Hepatol. 2007;  22(suppl 1) S7-S10
    CrossrefPubMedGoogle Scholar
  • 54 Lu Y, Cederbaum A I. CYP2E1 and oxidative liver injury by alcohol.  Free Radic Biol Med. 2008;  44(5) 723-738
    CrossrefPubMedGoogle Scholar
  • 55 Lieber C S, DeCarli L M. The role of the hepatic microsomal ethanol oxidizing system (MEOS) for ethanol metabolism in vivo.  J Pharmacol Exp Ther. 1972;  181(2) 279-287
    PubMedGoogle Scholar
  • 56 Lieber C S. Cytochrome P-4502E1: its physiological and pathological role.  Physiol Rev. 1997;  77(2) 517-544
    PubMedGoogle Scholar
  • 57 Badger T M, Ronis M J, Seitz H K et al.. Alcohol metabolism: role in toxicity and carcinogenesis.  Alcohol Clin Exp Res. 2003;  27(2) 336-347
    CrossrefPubMedGoogle Scholar
  • 58 Harada S, Agarwal D P, Nomura F, Higuchi S. Metabolic and ethnic determinants of alcohol drinking habits and vulnerability to alcohol-related disorder.  Alcohol Clin Exp Res. 2001;  25(suppl) 71S-75S
    PubMedGoogle Scholar
  • 59 Farke W, Anderson P. Binge drinking in Europe.  Adicciones. 2007;  19(4) 333-339
    PubMedGoogle Scholar
  • 60 Garretsen H F, Rodenburg G, van de Goor L A, van den Eijnden R J. Alcohol consumption in The Netherlands in the last decade: sharp decreases in binge drinking, especially among youngsters.  Alcohol Alcohol. 2008;  43(4) 477-480
    PubMedGoogle Scholar
  • 61 Koop D R. Oxidative and reductive metabolism by cytochrome P450 2E1.  FASEB J. 1992;  6(2) 724-730
    PubMedGoogle Scholar
  • 62 Zima T, Kalousova M. Oxidative stress and signal transduction pathways in alcoholic liver disease.  Alcohol Clin Exp Res. 2005;  29(11, Suppl) 110S-115S
    CrossrefPubMedGoogle Scholar
  • 63 Baan R, Straif K, Grosse Y et al.. Carcinogenicity of alcoholic beverages.  Lancet Oncol. 2007;  8(4) 292-293
    CrossrefPubMedGoogle Scholar
  • 64 Brooks P J, Theruvathu J A. DNA adducts from acetaldehyde: implications for alcohol-related carcinogenesis.  Alcohol. 2005;  35(3) 187-193
    CrossrefPubMedGoogle Scholar
  • 65 Lenaz G. The mitochondrial production of reactive oxygen species: mechanisms and implications in human pathology.  IUBMB Life. 2001;  52(3–5) 159-164
    CrossrefPubMedGoogle Scholar
  • 66 Tanaka E, Terada M, Misawa S. Cytochrome P450 2E1: its clinical and toxicological role.  J Clin Pharm Ther. 2000;  25(3) 165-175
    CrossrefPubMedGoogle Scholar
  • 67 Marrero J A, Fontana R J, Fu S et al.. Alcohol, tobacco and obesity are synergistic risk factors for hepatocellular carcinoma.  J Hepatol. 2005;  42(2) 218-224
    PubMedGoogle Scholar
  • 68 Vaca C E, Fang J L, Schweda E K. Studies of the reaction of acetaldehyde with deoxynucleosides.  Chem Biol Interact. 1995;  98(1) 51-67
    CrossrefPubMedGoogle Scholar
  • 69 Fang J L, Vaca C E. 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;  16(9) 2177-2185
    CrossrefPubMedGoogle Scholar
  • 70 Friedberg E C, Wagner R, Radman M. Specialized DNA polymerases, cellular survival, and the genesis of mutations.  Science. 2002;  296(5573) 1627-1630
    CrossrefPubMedGoogle Scholar
  • 71 Wang M, McIntee E J, Cheng G et al.. Identification of DNA adducts of acetaldehyde.  Chem Res Toxicol. 2000;  13(11) 1149-1157
    CrossrefPubMedGoogle Scholar
  • 72 de los Santos C, Zaliznyak T, Johnson F. NMR characterization of a DNA duplex containing the major acrolein-derived deoxyguanosine adduct gamma-OH-1,-N2-propano-2'-deoxyguanosine.  J Biol Chem. 2001;  276(12) 9077-9082
    CrossrefPubMedGoogle Scholar
  • 73 Kuykendall J R, Bogdanffy M S. Reaction kinetics of DNA-histone crosslinking by vinyl acetate and acetaldehyde.  Carcinogenesis. 1992;  13(11) 2095-2100
    CrossrefPubMedGoogle Scholar
  • 74 Mao H, Schnetz-Boutaud N C, Weisenseel J P, Marnett L J, Stone M P. Duplex DNA catalyzes the chemical rearrangement of a malondialdehyde deoxyguanosine adduct.  Proc Natl Acad Sci U S A. 1999;  96(12) 6615-6620
    CrossrefPubMedGoogle Scholar
  • 75 Fausto N, Campbell J S, Riehle K J. Liver regeneration.  Hepatology. 2006;  43(suppl 1) S45-S53
    CrossrefPubMedGoogle Scholar
  • 76 Koniaris L G, McKillop I H, Schwartz S I, Zimmers T A. Liver regeneration.  J Am Coll Surg. 2003;  197(4) 634-659
    CrossrefPubMedGoogle Scholar
  • 77 Michalopoulos G K. Liver regeneration.  J Cell Physiol. 2007;  213(2) 286-300
    CrossrefPubMedGoogle Scholar
  • 78 Niemela O. Aldehyde-protein adducts in the liver as a result of ethanol-induced oxidative stress.  Front Biosci. 1999;  4 D506-D513
    CrossrefPubMedGoogle Scholar
  • 79 Freeman T L, Tuma D J, Thiele G M et al.. Recent advances in alcohol-induced adduct formation.  Alcohol Clin Exp Res. 2005;  29(7) 1310-1316
    CrossrefPubMedGoogle Scholar
  • 80 Tuma D J. Role of malondialdehyde-acetaldehyde adducts in liver injury.  Free Radic Biol Med. 2002;  32(4) 303-308
    CrossrefPubMedGoogle Scholar
  • 81 Halsted C H, Villanueva J, Chandler C J et al.. Centrilobular distribution of acetaldehyde and collagen in the ethanol-fed micropig.  Hepatology. 1993;  18(4) 954-960
    CrossrefPubMedGoogle Scholar
  • 82 Niemela O, Juvonen T, Parkkila S. Immunohistochemical demonstration of acetaldehyde-modified epitopes in human liver after alcohol consumption.  J Clin Invest. 1991;  87(4) 1367-1374
    CrossrefPubMedGoogle Scholar
  • 83 Niemela O, Parkkila S, Yla-Herttuala S et al.. Covalent protein adducts in the liver as a result of ethanol metabolism and lipid peroxidation.  Lab Invest. 1994;  70(4) 537-546
    PubMedGoogle Scholar
  • 84 Bedossa P, Houglum K, Trautwein C, Holstege A, Chojkier M. Stimulation of collagen alpha 1(I) gene expression is associated with lipid peroxidation in hepatocellular injury: a link to tissue fibrosis?.  Hepatology. 1994;  19(5) 1262-1271
    CrossrefPubMedGoogle Scholar
  • 85 Casini A, Cunningham M, Rojkind M, Lieber C S. Acetaldehyde increases procollagen type I and fibronectin gene transcription in cultured rat fat-storing cells through a protein synthesis-dependent mechanism.  Hepatology. 1991;  13(4) 758-765
    CrossrefPubMedGoogle Scholar
  • 86 Friedman S L. Seminars in medicine of the Beth Israel Hospital, Boston. The cellular basis of hepatic fibrosis. Mechanisms and treatment strategies.  N Engl J Med. 1993;  328(25) 1828-1835
    CrossrefPubMedGoogle Scholar
  • 87 Bai J, Cederbaum A I. Mitochondrial catalase and oxidative injury.  Biol Signals Recept. 2001;  10(3–4) 189-199
    CrossrefPubMedGoogle Scholar
  • 88 Sato N. Central role of mitochondria in metabolic regulation of liver pathophysiology.  J Gastroenterol Hepatol. 2007;  22(Suppl 1) S1-S6
    CrossrefPubMedGoogle Scholar
  • 89 Abraham P, Wilfred G, Ramakrishna B. Oxidative damage to the hepatocellular proteins after chronic ethanol intake in the rat.  Clin Chim Acta. 2002;  325(1–2) 117-125
    CrossrefPubMedGoogle Scholar
  • 90 Amici A, Levine R L, Tsai L, Stadtman E R. Conversion of amino acid residues in proteins and amino acid homopolymers to carbonyl derivatives by metal-catalyzed oxidation reactions.  J Biol Chem. 1989;  264(6) 3341-3346
    PubMedGoogle Scholar
  • 91 Bondoc F Y, Bao Z, Hu W Y et al.. Acetone catabolism by cytochrome P450 2E1: studies with CYP2E1-null mice.  Biochem Pharmacol. 1999;  58(3) 461-463
    CrossrefPubMedGoogle Scholar
  • 92 Koop D R, Casazza J P. Identification of ethanol-inducible P-450 isozyme 3a as the acetone and acetol monooxygenase of rabbit microsomes.  J Biol Chem. 1985;  260(25) 13607-13612
    PubMedGoogle Scholar
  • 93 Laethem R M, Balazy M, Falck J R, Laethem C L, Koop D R. Formation of 19(S)-, 19(R)-, and 18(R)-hydroxyeicosatetraenoic acids by alcohol-inducible cytochrome P450 2E1.  J Biol Chem. 1993;  268(17) 12912-12918
    PubMedGoogle Scholar
  • 94 Guengerich F P, Shimada T, Yun C H et al.. Interactions of ingested food, beverage, and tobacco components involving human cytochrome P4501A2, 2A6, 2E1, and 3A4 enzymes.  Environ Health Perspect. 1994;  102(Suppl 9) 49-53
    PubMedGoogle Scholar
  • 95 Yang C S, Yoo J S, Ishizaki H, Hong J Y. Cytochrome P450IIE1: roles in nitrosamine metabolism and mechanisms of regulation.  Drug Metab Rev. 1990;  22(2–3) 147-159
    CrossrefPubMedGoogle Scholar
  • 96 Kushnareva Y, Murphy A N, Andreyev A. Complex I-mediated reactive oxygen species generation: modulation by cytochrome c and NAD(P) + oxidation-reduction state.  Biochem J. 2002;  368(Pt 2) 545-553
    CrossrefPubMedGoogle Scholar
  • 97 Garcia-Ruiz C, Fernandez-Checa J C. Mitochondrial glutathione: hepatocellular survival-death switch.  J Gastroenterol Hepatol. 2006;  21(Suppl 3) S3-S6
    CrossrefPubMedGoogle Scholar
  • 98 Lash L H. Mitochondrial glutathione transport: physiological, pathological and toxicological implications.  Chem Biol Interact. 2006;  163(1–2) 54-67
    CrossrefPubMedGoogle Scholar
  • 99 Fernandez-Checa J C, Kaplowitz N, Garcia-Ruiz C, Colell A. Mitochondrial glutathione: importance and transport.  Semin Liver Dis. 1998;  18(4) 389-401
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 100 Franco R, Schoneveld O J, Pappa A, Panayiotidis M I. The central role of glutathione in the pathophysiology of human diseases.  Arch Physiol Biochem. 2007;  113(4–5) 234-258
    CrossrefPubMedGoogle Scholar
  • 101 Lu S C. S-Adenosylmethionine.  Int J Biochem Cell Biol. 2000;  32(4) 391-395
    CrossrefPubMedGoogle Scholar
  • 102 Mato J M, Lu S C. Role of S-adenosyl-L-methionine in liver health and injury.  Hepatology. 2007;  45(5) 1306-1312
    CrossrefPubMedGoogle Scholar
  • 103 Lu S C, Mato J M. S-Adenosylmethionine in cell growth, apoptosis and liver cancer.  J Gastroenterol Hepatol. 2008;  23(suppl 1) S73-S77
    CrossrefPubMedGoogle Scholar
  • 104 Pascale R M, Simile M M, Seddaiu M A et al.. Chemoprevention of rat liver carcinogenesis by S-adenosyl-L-methionine: is DNA methylation involved?.  Basic Life Sci. 1993;  61 219-237
    PubMedGoogle Scholar
  • 105 Garcia-Ruiz C, Morales A, Colell A et al.. Feeding S-adenosyl-L-methionine attenuates both ethanol-induced depletion of mitochondrial glutathione and mitochondrial dysfunction in periportal and perivenous rat hepatocytes.  Hepatology. 1995;  21(1) 207-214
    CrossrefPubMedGoogle Scholar
  • 106 Lu S C, Mato J M. Role of methionine adenosyltransferase and S-adenosylmethionine in alcohol-associated liver cancer.  Alcohol. 2005;  35(3) 227-234
    CrossrefPubMedGoogle Scholar
  • 107 Mato J M, Camara J, Fernandez de Paz J et al.. S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial.  J Hepatol. 1999;  30(6) 1081-1089
    CrossrefPubMedGoogle Scholar
  • 108 Santini D, Vincenzi B, Massacesi C et al.. S-adenosylmethionine (AdoMet) supplementation for treatment of chemotherapy-induced liver injury.  Anticancer Res. 2003;  23(6D) 5173-5179
    PubMedGoogle Scholar
  • 109 Rambaldi A, Gluud C. S-adenosyl-L-methionine for alcoholic liver diseases.  Cochrane Database Syst Rev. 2006;  (2) CD002235
    PubMedGoogle Scholar
  • 110 Nagata K, Suzuki H, Sakaguchi S. Common pathogenic mechanism in development progression of liver injury caused by non-alcoholic or alcoholic steatohepatitis.  J Toxicol Sci. 2007;  32(5) 453-468
    CrossrefPubMedGoogle Scholar
  • 111 Thurman R G. II. Alcoholic liver injury involves activation of Kupffer cells by endotoxin.  Am J Physiol. 1998;  275(4 Pt 1) G605-G611
    PubMedGoogle Scholar
  • 112 Bode C, Bode J C. Activation of the innate immune system and alcoholic liver disease: effects of ethanol per se or enhanced intestinal translocation of bacterial toxins induced by ethanol?.  Alcohol Clin Exp Res. 2005;  29(suppl) 166S-171S
    CrossrefPubMedGoogle Scholar
  • 113 Hoek J B, Pastorino J G. Ethanol, oxidative stress, and cytokine-induced liver cell injury.  Alcohol. 2002;  27(1) 63-68
    CrossrefPubMedGoogle Scholar
  • 114 Hoek J B, Pastorino J G. Cellular signaling mechanisms in alcohol-induced liver damage.  Semin Liver Dis. 2004;  24(3) 257-272
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 115 Roberts R A, Ganey P E, Ju C et al.. Role of the Kupffer cell in mediating hepatic toxicity and carcinogenesis.  Toxicol Sci. 2007;  96(1) 2-15
    PubMedGoogle Scholar
  • 116 Thakur V, McMullen M R, Pritchard M T, Nagy L E. Regulation of macrophage activation in alcoholic liver disease.  J Gastroenterol Hepatol. 2007;  22(suppl 1) S53-S56
    CrossrefPubMedGoogle Scholar
  • 117 Ruttinger D, Vollmar B, Wanner G A, Messmer K. In vivo assessment of hepatic alterations following gadolinium chloride-induced Kupffer cell blockade.  J Hepatol. 1996;  25(6) 960-967
    CrossrefPubMedGoogle Scholar
  • 118 Vollmar B, Ruttinger D, Wanner G A, Leiderer R, Menger M D. Modulation of Kupffer cell activity by gadolinium chloride in endotoxemic rats.  Shock. 1996;  6(6) 434-441
    PubMedGoogle Scholar
  • 119 Friedman S L. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver.  Physiol Rev. 2008;  88(1) 125-172
    CrossrefPubMedGoogle Scholar
  • 120 Senoo H, Kojima N, Sato M. Vitamin A-storing cells (stellate cells).  Vitam Horm. 2007;  75 131-159
    PubMedGoogle Scholar
  • 121 Sato M, Suzuki S, Senoo H. Hepatic stellate cells: unique characteristics in cell biology and phenotype.  Cell Struct Funct. 2003;  28(2) 105-112
    CrossrefPubMedGoogle Scholar
  • 122 Parsons C J, Takashima M, Rippe R A. Molecular mechanisms of hepatic fibrogenesis.  J Gastroenterol Hepatol. 2007;  22(suppl 1) S79-S84
    CrossrefPubMedGoogle Scholar
  • 123 Albano E. Oxidative mechanisms in the pathogenesis of alcoholic liver disease.  Mol Aspects Med. 2008;  29(1–2) 9-16
    CrossrefPubMedGoogle Scholar
  • 124 Lirussi F, Azzalini L, Orando S, Orlando R, Angelico F. Antioxidant supplements for non-alcoholic fatty liver disease and/or steatohepatitis.  Cochrane Database Syst Rev. 2007;  (1) CD004996
    PubMedGoogle Scholar
  • 125 Karaa A, Thompson K J, McKillop I H, Clemens M G, Schrum L W. S-adenosyl-L-methionine attenuates oxidative stress and hepatic stellate cell activation in an ethanol-lps-induced fibrotic rat model.  Shock. 2008;  30(2) 197-205
    CrossrefPubMedGoogle Scholar
  • 126 Yang X, Lu P, Ishida Y et al.. Attenuated liver tumor formation in the absence of CCR2 with a concomitant reduction in the accumulation of hepatic stellate cells, macrophages and neovascularization.  Int J Cancer. 2006;  118(2) 335-345
    CrossrefPubMedGoogle Scholar
  • 127 Johnson S J, Burr A W, Toole K et al.. Macrophage and hepatic stellate cell responses during experimental hepatocarcinogenesis.  J Gastroenterol Hepatol. 1998;  13(2) 145-151
    CrossrefPubMedGoogle Scholar
  • 128 Reuben A. Alcohol and the liver.  Curr Opin Gastroenterol. 2006;  22(3) 263-271
    PubMedGoogle Scholar
  • 129 Colombo M, Sangiovanni A. Etiology, natural history and treatment of hepatocellular carcinoma.  Antiviral Res. 2003;  60(2) 145-150
    CrossrefPubMedGoogle Scholar
  • 130 Macdonald G A. Pathogenesis of hepatocellular carcinoma.  Clin Liver Dis. 2001;  5(1) 69-85
    CrossrefPubMedGoogle Scholar
  • 131 Okuda K. Hepatocellular carcinoma–history, current status and perspectives.  Dig Liver Dis. 2002;  34(9) 613-616
    CrossrefPubMedGoogle Scholar
  • 132 Ribatti D, Vacca A, Nico B, Sansonno D, Dammacco F. Angiogenesis and anti-angiogenesis in hepatocellular carcinoma.  Cancer Treat Rev. 2006;  32(6) 437-444
    CrossrefPubMedGoogle Scholar
  • 133 Pang R, Poon R T. Angiogenesis and antiangiogenic therapy in hepatocellular carcinoma.  Cancer Lett. 2006;  242(2) 151-167
    CrossrefPubMedGoogle Scholar
  • 134 Sugimachi K, Tanaka S, Taguchi K et al.. Angiopoietin switching regulates angiogenesis and progression of human hepatocellular carcinoma.  J Clin Pathol. 2003;  56(11) 854-860
    CrossrefPubMedGoogle Scholar
  • 135 Bauer I, Bauer M, Pannen B H et al.. Chronic ethanol consumption exacerbates liver injury following hemorrhagic shock: role of sinusoidal perfusion failure.  Shock. 1995;  4(5) 324-331
    CrossrefPubMedGoogle Scholar
  • 136 Bauer M, Paquette N C, Zhang J X et al.. Chronic ethanol consumption increases hepatic sinusoidal contractile response to endothelin-1 in the rat.  Hepatology. 1995;  22(5) 1565-1576
    CrossrefPubMedGoogle Scholar
  • 137 Karaa A, Kamoun W S, Clemens M G. Chronic ethanol sensitizes the liver to endotoxin via effects on endothelial nitric oxide synthase regulation.  Shock. 2005;  24(5) 447-454
    CrossrefPubMedGoogle Scholar
  • 138 Aroor A R, Shukla S D. MAP kinase signaling in diverse effects of ethanol.  Life Sci. 2004;  74(19) 2339-2364
    CrossrefPubMedGoogle Scholar
  • 139 Hoek J B, Rubin E. Alcohol and membrane-associated signal transduction.  Alcohol Alcohol. 1990;  25(2–3) 143-156
    PubMedGoogle Scholar
  • 140 Hoek J B, Thomas A P, Rooney T A, Higashi K, Rubin E. Ethanol and signal transduction in the liver.  FASEB J. 1992;  6(7) 2386-2396
    PubMedGoogle Scholar
  • 141 Ronis M J, Wands J R, Badger T M et al.. Alcohol-induced disruption of endocrine signaling.  Alcohol Clin Exp Res. 2007;  31(8) 1269-1285
    CrossrefPubMedGoogle Scholar
  • 142 Diehl A M, Yang S Q, Wolfgang D, Wand G. Differential expression of guanine nucleotide-binding proteins enhances cAMP synthesis in regenerating rat liver.  J Clin Invest. 1992;  89(6) 1706-1712
    CrossrefPubMedGoogle Scholar
  • 143 Diehl A M, Yang S Q, Cote P, Wand G S. Chronic ethanol consumption disturbs G-protein expression and inhibits cyclic AMP-dependent signaling in regenerating rat liver.  Hepatology. 1992;  16(5) 1212-1219
    PubMedGoogle Scholar
  • 144 McKillop I H, Wu Y, Cahill P A, Sitzmann J V. Altered expression of inhibitory guanine nucleotide regulatory proteins (Gi-proteins) in experimental hepatocellular carcinoma.  J Cell Physiol. 1998;  175(3) 295-304
    CrossrefPubMedGoogle Scholar
  • 145 Schmidt C M, McKillop I H, Cahill P A, Sitzmann J V. Alterations in guanine nucleotide regulatory protein expression and activity in human hepatocellular carcinoma.  Hepatology. 1997;  26(5) 1189-1194
    CrossrefPubMedGoogle Scholar
  • 146 McKillop I H, Vyas N, Schmidt C M, Cahill P A, Sitzmann J V. Enhanced Gi-protein-mediated mitogenesis following chronic ethanol exposure in a rat model of experimental hepatocellular carcinoma.  Hepatology. 1999;  29(2) 412-420
    CrossrefPubMedGoogle Scholar

Iain H McKillopPh.D. 

Department of General Surgery, Carolinas Medical Center

1000 Blythe Boulevard, Charlotte, NC 28203

eMail: iain.mckillop@carolinashealthcare.org