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Alcohol and cancer: genetic and nutritional aspects

Published online by Cambridge University Press:  07 March 2007

Gudrun Pöschl ,
Felix Stickel ,
Xiang D. Wang  and
Helmut K. Seitz
Gudrun Pöschl
Affiliation:
Laboratory of Alcohol Research, Liver Disease and Nutrition and Department of Medicine, Salem Medical Center, Zeppelinstraße 11-33, 69121 Heidelberg, Germany
Felix Stickel
Affiliation:
Department of Medicine I, University of Erlangen – Nürnberg, Erlangen, Germany
Xiang D. Wang
Affiliation:
USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington St, Boston, MA 02111, USA
Helmut K. Seitz*
Affiliation:
Laboratory of Alcohol Research, Liver Disease and Nutrition and Department of Medicine, Salem Medical Center, Zeppelinstraße 11-33, 69121 Heidelberg, Germany
*
*Corresponding author: Professor Helmut K. Seitz, fax + 49 6221 483494, email [email protected]
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Abstract

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Chronic alcohol consumption is a major risk factor for cancer of upper aero-digestive tract (oro-pharynx, hypopharynx, larynx and oesophagus), the liver, the colo-rectum and the breast. Evidence has accumulated that acetaldehyde is predominantly responsible for alcohol-associated carcinogenesis. Acetaldehyde is carcinogenic and mutagenic, binds to DNA and protein, destroys the folate molecule and results in secondary cellular hyper-regeneration. Acetaldehyde is produced by mucosal and cellular alcohol dehydrogenase, cytochrome P450 2E1 and through bacterial oxidation. Its generation and/or its metabolism is modulated as a result of polymorphisms or mutations of the genes responsible for these enzymes. Acetaldehyde can also be produced by oral bacteria. Smoking, which changes the oral bacterial flora, also increases salivary acetaldehyde. Cigarette smoke and some alcoholic beverages, such as Calvados, contain acetaldehyde. In addition, chronic alcohol consumption induces cytochrome P450 2E1 enxyme activity in mucosal cells, resulting in an increased generation of reactive oxygen species and in an increased activation of various dietary and environmental carcinogens. Deficiencies of riboflavin, Zn, folate and possibly retinoic acid may further enhance alcohol-associated carcinogenesis. Finally, methyl deficiency as a result of multiple alcohol-induced changes leads to DNA hypomethylation. A depletion of lipotropes, including methionine, choline, betaine and S-adenosylmethionine, as well as folate, results in the hypomethylation of oncogenes and may lead to DNA strand breaks, all of which are associated with increased carcinogenesis.

Keywords

Chronic alcohol consumptionCancerAcetaldehydeCytochrome P450 2E1Alcohol–nutrient interactions
Type
Meeting Report
Information
Proceedings of the Nutrition Society , Volume 63 , Issue 1 , February 2004 , pp. 65 - 71
Copyright
Copyright © The Nutrition Society 2004

References

Albano, E & Clot, P (1996) Free radicals and ethanol toxicity. In Alcohol and the Gastrointestinal Tract 57 – 68 [Preedy, VR, Watson, RR] Boca Raton, FL CRC PressGoogle Scholar
Anonymous, (1985) Acetaldehyde IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans 36, 101–132.Google Scholar
Barak, AJ, Beckenhauer, HC, Hidiroglou, N, Camilo, ME, Selhub, J & Tuma, DJ (1993) The relationship of ethanol feeding to the methyl folate trap. Alcohol 10, 495–497.CrossRefGoogle Scholar
Borras, E, Coutelle, C, Rosell, A, Fernandez-Muixi, F, Broch, M, Crosas, B et al. (2000) Genetic polymorphism of alcohol dehydrogenase in Europeans: the ADH2*2 allele decreases the risk for alcoholism and is associated with ADH3*1 Hepatology 31, 984–989.CrossRefGoogle ScholarPubMed
Chen, N, Nomura, M, She, QB, Ma, WY, Bode, AM, Wang, L, Flavell, RA & Dong, Z (2001) Suppression of skin tumorigenesis in c-JUN NH(2)-terminal kinase-2-deficient mice Cancer Research 61, 3908–3912.Google ScholarPubMed
Choi, SW, Stickel, F, Baik, HW, Kim, YI, Seitz, HK & Mason, JB (1999) Chronic alcohol consumption induces genomic but not p53-specific DNA hypomethylation in rat colon. Journal of Nutrition 129, 1945–1950.CrossRefGoogle Scholar
Chung, J, Chavez, PR, Russell, RM & Wang, XD (2002) Retinoic acid inhibits hepatic Jun N-terminal kinase-dependent signaling pathway in ethanol-fed rats Oncogene 21, 1539–1547.Google Scholar
Chung, J, Liu, C, Smith, DE, Seitz, HK, Russell, RM & Wang, XD (2001) Restoration of retinoic acid concentration suppresses ethanol-enhanced c-Jun expression and hepatocyte proliferation in rat liver. Carcinogenesis 22, 1213–1219.CrossRefGoogle ScholarPubMed
Counts, JL & Goodman, JI (1995) Alterations in DNA methylation play a variety of roles in carcinogenesis. Cell 83, 13–15.CrossRefGoogle ScholarPubMed
Coutelle, C, Ward, PJ, Fleury, B, Quattrocchi, P, Chambrin, H, Iron, A, Couzigou, P & Cassaigne, A (1997) Laryngeal and oropharyngeal cancer, and alcohol dehydrogenase 3 and glutathione S-transferase M1 polymorphisms. Human Genetics 99, 319–325.Google Scholar
Crabb, DW, Pinairs, J, Hasanadka, R, Fang, M, Leo, MA, Lieber, CS, et al. (2001) Alcohol and retinoids. Alcohol, Clinical and Experimental Research 25, 207S–217S.CrossRefGoogle ScholarPubMed
Dellarco, VL (1988) A mutagenicity assessment of acetaldehyde. Mutation Research 195, 1–20.CrossRefGoogle ScholarPubMed
Eskelson, CD, Odeleye, OE, Watson, RR, Earnest, DL & Mufti, SI (1993) Modulation of cancer growth by vitamin E and alcohol. Alcohol and Alcoholism 28, 117–126.Google ScholarPubMed
Espina, N, Lima, V, Lieber, CS & Garro, AJ (1988) In vitro and in vivo inhibitory effect of ethanol and acetaldehyde on O 6 -methylguanine transferase. Carcinogenesis 9, 761–766.CrossRefGoogle Scholar
Fang, JL & Vaca, CE (1995) Development of a 32P-postlabeling method for the analysis of adducts arising through the reaction of acetaldehyde with 2'-deoxyguanosine-3'-monophosphate and DNA. Carcinogenesis 16, 2177–2185.Google Scholar
Fang, JL & Vaca, CE (1997) Detection of DNA adducts of acetaldehyde in peripheral white blood cells of alcohol abusers. Carcinogenesis 18, 627–632.Google Scholar
Garro, AJ McBeth, DL Lima, V, Lieber, CS (1991) Ethanol consumption inhibits fetal DNA methylation in mice: implications for the fetal alcohol syndrome. Alcohol, Clinical and Experimental Research 15, 395–398.CrossRefGoogle ScholarPubMed
Gloria, L, Cravo, M, Camilo, ME, Resende, M, Cardoso, JN, Oliveira, AG, Leitao, CN & Mira, FC (1997) Nutritional deficiencies in chronic alcoholics: relation to dietary intake and alcohol consumption. American Journal of Gastroenterology 92, 485–489.Google ScholarPubMed
Gouillon, Z, Lucas, D, Li, J, Hagbjork, AL, French, BA, Fu, P, Fang, C, Ingelman-Sundberg, M, Donohue, TM Jr & French, SW (2000) Inhibition of ethanol-induced liver disease in the intragastric feeding rat model by chlormethiazole. Proceedings of the Society for Experimental Biology and Medicine 224, 302–308.Google ScholarPubMed
Grummer, MA & Zachman, RD (2000) Interaction of ethanol with retinol and retinoic acid in RAR beta and GAP-43 expression. Neurotoxicology and Teratology 22, 829–836.CrossRefGoogle ScholarPubMed
Halsted, CH, Villanueva, J, Chandler, CJ, Stabler, SP, Allen, RH, Muskhelishvili, L, James, SJ & Poirier, L (1996) Ethanol feeding of micropigs alters methionine metabolism and increases hepatocellular apoptosis and proliferation. Hepatology 23, 497–505.Google Scholar
Harty, LC, Caporaso, NE, Hayes, RB, Winn, DM, Bravo-Otero, E, Blot, WJ, Kleinman, DV, Brown, LM, Armenian, HK, Fraumeni, JF Jr & Shields, PG (1997) Alcohol dehydrogenase 3 genotype and risk of oral cavity and pharyngeal cancers. Journal of the National Cancer Institute 89, 1698–1705.Google Scholar
Helander, A & Lindahl-Kiessling, K (1991) Increased frequency of acetaldehyde-induced sister-chromatide exchanges in human lymphocytes treated with an aldehyde dehydrogenase inhibitor. Mutatation Research 264, 103–107.Google Scholar
Homann, N, Jousimies-Somer, H, Jokelainen, K, Heine, R & Salaspuro, M (1997a) High acetaldehyde levels in saliva after ethanol consumption: Methodological aspects and pathogenetic implications. Carcinogenesis 18, 1739–1743.Google Scholar
Homann, N, Karkkainen, P, Koivisto, T, Nosova, T, Jokelainen, K & Salaspuro, M (1997b) Effects of acetaldehyde on cell regeneration and differentiation of the upper gastrointestinal tract mucosa. Journal of the National Cancer Institute 89, 1692–1697.Google Scholar
Homann, N, Tillonen, J, Meurman, JH, Rintamaki, H, Lindqvist, C, Rautio, M, Jousimies-Somer, H & Salaspuro, M (2000) Increased salivary acetaldehyde levels in heavy drinkers and smokers: A microbiological approach to oral cavity cancer. Carcinogenesis 21, 663–668.Google Scholar
Homann, N, Tillonen, J, Rintamaki, H, Salaspuro, M, Lindqvist, C & Meurman, JH (2001) Poor dental status increases the acetaldehyde production from ethanol in saliva. A possible link to the higher risk of oral cancer among alcohol consumers. Oral Oncology 37, 153–158.CrossRefGoogle Scholar
Hui, AM & Makuuchi, M (1999) Molecular basis of multistep hepatocarcinogenesis: genetic and epigenetic events. Scandinavian Journal of Gastroenterology 8, 737–742.Google Scholar
Iwata, N, Yamamoto, H, Sasaki, S, Itoh, F, Suzuki, H, Kikuchi, T et al. (2000) Frequent hypermethylation of CpG islands and loss of expression of the 14–3-3 sigma gene in human hepatocellular carcinoma. Oncogene 19, 5298–5302.CrossRefGoogle ScholarPubMed
Jokelainen, K, Heikkonen, E, Roine, R, Lehtonen, H & Salaspuro, M (1996) Increased acetaldehyde production by mouthwashings from patients with oral cavity, laryngeal, or pharyngeal cancer. Alcohol, Clinical and Experimental Research 20, 1206–1210.Google Scholar
Kanai, Y, Hui, AM, Sun, L, Ushijima, S, Sakamoto, M, Tsuda, H & Hirohashi, S (1999) DNA hypermethylation at the D17S5 locus and reduced HIC-1 mRNA expression are associated with hepatocarcinogenesis. Hepatology 29, 703–709.CrossRefGoogle ScholarPubMed
Kanai, Y, Ushijima, S, Tsuda, H, Sakamoto, M & Hirohashi, S (2000) Aberrant DNA methylation precedes loss of heterozygosity on chromosome 16 in chronic hepatitis and liver cirrhosis. Cancer Letters 148, 73–80.CrossRefGoogle ScholarPubMed
Kondo, Y, Kanai, Y, Sakamoto, M, Mizokami, M, Ueda, R & Hirohashi, S (2000) 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 32, 970–979.CrossRefGoogle ScholarPubMed
Labadarios, D, Rossouw, JE McConnell, JB Davis, M & Williams, R (1977) Vitamin B6 deficiency in chronic liver disease – evidence for increased degradation of pyridoxal-5'-phosphate. Gut 18, 23–27.CrossRefGoogle ScholarPubMed
Leo, MA, Kim, C & Lieber, CS (1986) Increased vitamin A in esophagus and other extrahepatic tissues after chronic ethanol consumption in the rat. Alcohol, Clinical and Experimental Research 10, 487–492.Google Scholar
Leo, MA & Lieber, CS (1982) Hepatic vitamin A depletion in alcoholic liver injury. New England Journal of Medicine 307, 597–601.CrossRefGoogle ScholarPubMed
Li, JJ, Benesova, M, Goette, K, Fiehn, W, Conradt, C, Hoermann, K, Salaspuro, M & Seitz, HK (2001) Enhanced risk of upper alimentary tract cancer in patients with the alcohol dehydrogenase 3*1 allele due to increased salivary acetaldehyde following ethanol ingestion. Gastroenterology 120 A-160.CrossRefGoogle Scholar
Lieber, CS (1994a) Mechanisms of ethanol-drug nutrition interactions. Journal of Toxicology Clinical Toxicology 32, 631–681.CrossRefGoogle ScholarPubMed
Lieber, CS (1994b) Alcohol and the liver: 1994 update. Gastroenterology 106, 1085–1105.Google Scholar
Lieber, CS, Casini, A DeCarli, LM Kim, CI, Lowe, N, Sasaki, R & Leo, MA (1990) S -adenosyl-L-methionine attenuates alcohol-induced liver injury in the baboon. Hepatology 11, 165–172.Google Scholar
Lippman, SM & Lotan, R (2000) Advances in the development of retinoids as chemopreventive agents. Journal of Nutrition 130, 479S–482S.Google Scholar
Liu, C, Chung, J, Seitz, HK, Russell, RM & Wang, XD (2002) Chlormethiazole treatment prevents reduced hepatic vitamin A levels in alcohol-fed rats. Alcohol, Clinical and Experimental Research 26, 1703–1709.CrossRefGoogle Scholar
Liu, C, Russell, RM, Seitz, HK & Wang, XD (2001) Ethanol enhances retinoic acid metabolism into polar metabolites in rat liver via induction of cytochrome P450 2E1. Gastroenterology 120, 179–189.CrossRefGoogle Scholar
Lumeng, L & Li, TK (1974) Vitamin B6 metabolism in chronic alcohol abuse. Journal of Clinical Investigations 53, 693–704.Google Scholar
Maier, H, Born, IA, Veith, S, Adler, D & Seitz, HK (1986) The effect of chronic ethanol consumption on salivary gland morphology and function in the rat. Alcohol, Clinical and Experimental Research 10, 425–427.Google Scholar
Matsuda, T, Terashima, I, Matsumoto, Y, Yabushita, H, Matsui, S & Shibutani, S (1999) Effective utilization of N2-ethyl-2'-deoxyguanosine triphosphate during DNA synthesis catalyzed by mammalian replicative DNA polymerases. Biochemistry 38, 929–935.Google Scholar
Miyakawa, H, Liu, J, Noguchi, O, Marumo, F & Sato, C (1996) Effect of alcohol drinking on gene expression of hepatic O 6 -methylguanine DNA methyltransferase in chronic liver diseases. Alcohol, Clinical and Experimental Research 20, 297A–300A.CrossRefGoogle ScholarPubMed
Mobarhan, S, Seitz, HK, Russell, RM, Mehta, R, Hupert, J, Friedman, H, Layden, TJ, Meydani, M & Langenberg, P (1991) Age-related effects of chronic ethanol intake on vitamin A status in Fisher 344 rats. Journal of Nutrition 121, 510–517.Google Scholar
Olshan, AF, Weissler, MC, Watson, MA & Bell, DA (2001) Risk of head and neck cancer and the alcohol dehydrogenase 3 genotype. Carcinogenesis 22, 57–61.Google Scholar
Oneta, CM, Lieber, CS, Li, J, Ruttimann, S, Schmid, B, Lattmann, J, Rosman, AS & Seitz, HK (2002) Dynamics of cytochrome P450 2E1 activity in man: induction by ethanol and disappearance during withdrawal phase. Journal of Hepatology 36, 47–52.CrossRefGoogle ScholarPubMed
Pogribny, IP, Basnakian, AG, Miller, BJ, Lopatina, NG, Poirier, LA & James, SJ (1995) Breaks in genomic DNA and within the p53 gene are associated with hypomethylation in livers of folate/methyl-deficient rats. Cancer Research 55, 1894–1901.Google ScholarPubMed
Salaspuro, MP (2003) Acetaldehyde, microbes, and cancer of the digestive tract. Critical Reviews in Clinical Laboratory Science 40, 183–208.Google Scholar
Sato, M & Lieber, CS (1982) Increased metabolism of retinoic acid after chronic ethanol consumption in rat liver microsomes. Archives of Biochemistry and Biophysics 213, 557–564.CrossRefGoogle ScholarPubMed
Savage, D & Lindenbaum, J (1986) Anemia in alcoholics. Medicine 56, 322–328.Google Scholar
Seitz, HK, Matsuzaki, S, Yokoyama, A, Homann, N, Vakevainen, S & Wang, XD (2001) Alcohol and cancer. Alcohol, Clinical and Experimental Research 25, 137–143.Google Scholar
Seitz, HK & Oneta, CM (1998) Gastrointestinal alcohol dehydrogenases. Nutrition Reviews 56, 52–60.Google Scholar
Seitz, HK & Oswald, BR (1992) Effect of ethanol on procarcinogen activation. In Alcohol and Cancer, pp55 – 72 [Watson, RReditor]. Boca Raton, FL CRC PressGoogle Scholar
Seitz, HK, Pöschl, G & Simanowski, UA (1998) Alcohol and cancer. Recent Developments in Alcoholism 14, 67–95.CrossRefGoogle ScholarPubMed
Shen, L, Fang, J, Qiu, D, Zhang, T, Yang, J, Chen, S & Xiao, S (1998) Correlation between DNA methylation and pathological changes in human hepatocellular carcinoma. Hepatogastroenterology 45, 1753–1759.Google Scholar
Shimizu, M, Lasker, JM, Tsutsumi, M & Lieber, CS (1990) Immunohistochemical localization of ethanol-inducible P450 2E1 in the rat alimentary tract. Gastroenterology 99, 1044–1053.CrossRefGoogle Scholar
Simanowski, UA, Suter, P, Stickel, F, Maier, H, Waldherr, R, Smith, D, Russell, RM & Seitz, HK (1993) Esophageal epithelial hyperregeneration following chronic ethanol ingestion: Effect of age and salivary gland function. Journal of the National Cancer Institute 85, 2030–2033.CrossRefGoogle Scholar
Simoni, D, Tolomeo, M (2001) Retinoids, apoptosis and cancer. Current Pharmaceutical Design 7, 1823–1837.CrossRefGoogle ScholarPubMed
Speisky, H MacDonald, A Giles, G, Orrego, H & Israel, Y (1985) Increased loss and decreased synthesis of hepatic glutathione after acute ethanol administration. Turnover studies. Biochemical Journal 225, 565–572.Google Scholar
Stickel, F, Choi, SW, Kim, YI, Bagley, PJ, Seitz, HK, Russell, RM, Selhub, J & Mason, JB (2000) Effect of chronic alcohol consumption on total plasma homocysteine level in rats. Alcohol, Clinical and Experimental Research 24, 259–264.CrossRefGoogle ScholarPubMed
Stickel, F, Homann, N, Benesova, M, Jacobs, A, Schuppan, D, Hahn, EG, Conradt, C, Ludwig, D, Zuber, I, Blum, HE & Seitz, HK (2003) Genetic predisposition for alcohol associated upper aerodigestive tract cancer and hepatocellular cancer in heavy drinkers with the alcohol dehydrogenase 3*1 allele. Gastroenterology 124 A547Google Scholar
Sturgis, EM, Dahlstrom, KR, Guan, Y, Eicher, SA, Strom, SS, Spitz, MR & Wei, Q (2001) Alcohol dehydrogenase 3 genotype is not associated with risk of squamous cell carcinoma of the oral cavity and pharynx. Cancer Epidemiology, Biomarkers and Prevention 10, 273–275.Google Scholar
Trimble, KC, Molloy, AM, Scott, JM & Weir, DG (1993) The effect of ethanol on one-carbon metabolism: increased methionine catabolism and lipotrope methyl-group wastage. Hepatology 18, 984–989.Google Scholar
Uto, H, Ido, A, Moriuchi, A, Onaga, Y, Nagata, K, Onaga, M, Tahara, Y, Hori, T, Hirono, S, Hayashi, K & Tsubouchi, H (2001) Transduction of antisense cyclin D1 using two-step gene transfer inhibits the growth of rat hepatoma cells. Cancer Research 61, 4779–4783.Google Scholar
Vakevainen, S, Tillonen, J, Agarwal, DP, Srivastava, N & Salaspuro, M (2000) High salivary acetaldehyde after a moderate dose of alcohol in ALDH2-deficient subjects: strong evidence for the local carcinogenic action of acetaldehyde. Alcohol, Clinical and Experimental Research 24, 873–877.Google Scholar
Wainfan, E, Dizik, M, Stender, M & Christman, JK (1989) Rapid appearance of hypomethylated DNA in livers of rats fed cancer-promoting, methyl-deficient diets. Cancer Research 49, 4094–4097.Google ScholarPubMed
Wang, XD (2001) Retinoids and alcoholic liver disease Alcohol in Health and Disease 427 – 452 Agarwal, DP, Seitz, HK, New York: Marcel Dekker.Google Scholar
Wang, XD, Liu, C, Chung, J, Stickel, F, Seitz, HK & Russell, RM (1998) Chronic alcohol intake reduces retinoic acid concentration and enhances AP-1 (c-JUN and c-FOS) expression in rat liver. Hepatology 28, 744–750.Google Scholar
Woutersen, RA, Appelman, LM, Van Garderen-Hoetmer, A & Feron, VJ (1986) Inhalation toxicity of acetaldehyde in rats: III. Carcinogenicity study. Toxicology 41, 213–231.Google Scholar
Yokoyama, A, Muramatsu, T, Ohmori, T, Makuuchi, H, Higuchi, S, Matsushita, S, Yoshino, K, Maruyama, K, Nakano, M & Ishii, H (1996) Multiple primary esophageal and concurrent aerodigestive tract cancer and the aldehyde dehydrogenase-2 genotype of Japanese alcoholics. Cancer 77, 1986–1990.3.0.CO;2-F>CrossRefGoogle ScholarPubMed
Yokoyama, A, Muramatsu, T & Ohmori, T (1998) Alcohol related cancers and aldehyde dehydrogenase in Japanese alcoholics. Carcinogenesis 19, 1383–1387.Google Scholar
Yokoyama, A, Muramatsu, T, Omori, T, Matsushita, S, Yoshimizu, H, Higuchi, S, Yokoyama, T, Maruyama, K & Ishii, H (1999) Alcohol and aldehyde gene polymorphisms influence susceptibility to esophageal cancer in Japanese alcoholics. Alcohol, Clinical and Experimental Research 23, 1705–1710.Google Scholar
Young, MR, Li, JJ, Rincon, M, Flavell, RA, Sathyanarayana, BK, Hunziker, R & Colburn, N (1999) Transgenic mice demonstrate AP-1 (activator protein 1) transactivation is required for tumor promotion. Proceedings of the National Academy of Sciences USA 96, 9827–9832.CrossRefGoogle ScholarPubMed
Zapisek, WF & Cronin, GM Lyn-Cook, BD Poirier, LA (1992) The onset of oncogene hypomethylation in the livers of rats fed methyl-deficient, amino acid-defined diets. Carcinogenesis 13, 1869–1872.Google Scholar
Albano, E & Clot, P (1996) Free radicals and ethanol toxicity. In Alcohol and the Gastrointestinal Tract 57 – 68 [Preedy, VR, Watson, RR] Boca Raton, FL CRC PressGoogle Scholar
Anonymous, (1985) Acetaldehyde IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans 36, 101–132.Google Scholar
Barak, AJ, Beckenhauer, HC, Hidiroglou, N, Camilo, ME, Selhub, J & Tuma, DJ (1993) The relationship of ethanol feeding to the methyl folate trap. Alcohol 10, 495–497.CrossRefGoogle Scholar
Borras, E, Coutelle, C, Rosell, A, Fernandez-Muixi, F, Broch, M, Crosas, B et al. (2000) Genetic polymorphism of alcohol dehydrogenase in Europeans: the ADH2*2 allele decreases the risk for alcoholism and is associated with ADH3*1 Hepatology 31, 984–989.Google Scholar
Chen, N, Nomura, M, She, QB, Ma, WY, Bode, AM, Wang, L, Flavell, RA & Dong, Z (2001) Suppression of skin tumorigenesis in c-JUN NH(2)-terminal kinase-2-deficient mice. Cancer Research 61, 3908–3912.Google ScholarPubMed
Choi, SW, Stickel, F, Baik, HW, Kim, YI, Seitz, HK & Mason, JB (1999) Chronic alcohol consumption induces genomic but not p53-specific DNA hypomethylation in rat colon. Journal of Nutrition 129, 1945–1950.Google Scholar
Chung, J, Chavez, PR, Russell, RM & Wang, XD (2002) Retinoic acid inhibits hepatic Jun N-terminal kinase-dependent signaling pathway in ethanol-fed rats Oncogene 21, 1539–1547.CrossRefGoogle ScholarPubMed
Chung, J, Liu, C, Smith, DE, Seitz, HK, Russell, RM & Wang, XD (2001) Restoration of retinoic acid concentration suppresses ethanol-enhanced c-Jun expression and hepatocyte proliferation in rat liver. Carcinogenesis 22, 1213–1219.CrossRefGoogle ScholarPubMed
Counts, JL & Goodman, JI (1995) Alterations in DNA methylation play a variety of roles in carcinogenesis. Cell 83, 13–15.Google Scholar
Coutelle, C, Ward, PJ, Fleury, B, Quattrocchi, P, Chambrin, H, Iron, A, Couzigou, P & Cassaigne, A (1997) Laryngeal and oropharyngeal cancer, and alcohol dehydrogenase 3 and glutathione S-transferase M1 polymorphisms. Human Genetics 99, 319–325.Google Scholar
Crabb, DW, Pinairs, J, Hasanadka, R, Fang, M, Leo, MA, Lieber, CS, et al. (2001) Alcohol and retinoids. Alcohol, Clinical and Experimental Research 25, 207S–217S.CrossRefGoogle ScholarPubMed
Dellarco, VL (1988) A mutagenicity assessment of acetaldehyde. Mutation Research 195, 1–20.Google Scholar
Eskelson, CD, Odeleye, OE, Watson, RR, Earnest, DL & Mufti, SI (1993) Modulation of cancer growth by vitamin E and alcohol. Alcohol and Alcoholism 28, 117–126.Google Scholar
Espina, N, Lima, V, Lieber, CS & Garro, AJ (1988) In vitro and in vivo inhibitory effect of ethanol and acetaldehyde on O 6 -methylguanine transferase. Carcinogenesis 9, 761–766.Google Scholar
Fang, JL & Vaca, CE (1995) Development of a 32P-postlabeling method for the analysis of adducts arising through the reaction of acetaldehyde with 2'-deoxyguanosine-3'-monophosphate and DNA. Carcinogenesis 16, 2177–2185.CrossRefGoogle Scholar
Fang, JL & Vaca, CE (1997) Detection of DNA adducts of acetaldehyde in peripheral white blood cells of alcohol abusers. Carcinogenesis 18, 627–632.Google Scholar
Garro, AJ McBeth, DL Lima, V, Lieber, CS (1991) Ethanol consumption inhibits fetal DNA methylation in mice: implications for the fetal alcohol syndrome. Alcohol, Clinical and Experimental Research 15, 395–398.Google Scholar
Gloria, L, Cravo, M, Camilo, ME, Resende, M, Cardoso, JN, Oliveira, AG, Leitao, CN & Mira, FC (1997) Nutritional deficiencies in chronic alcoholics: relation to dietary intake and alcohol consumption. American Journal of Gastroenterology 92, 485–489.Google Scholar
Gouillon, Z, Lucas, D, Li, J, Hagbjork, AL, French, BA, Fu, P, Fang, C, Ingelman-Sundberg, M, Donohue, TM Jr & French, SW (2000) Inhibition of ethanol-induced liver disease in the intragastric feeding rat model by chlormethiazole. Proceedings of the Society for Experimental Biology and Medicine 224, 302–308.Google Scholar
Grummer, MA & Zachman, RD (2000) Interaction of ethanol with retinol and retinoic acid in RAR beta and GAP-43 expression. Neurotoxicology and Teratology 22, 829–836.Google Scholar
Halsted, CH, Villanueva, J, Chandler, CJ, Stabler, SP, Allen, RH, Muskhelishvili, L, James, SJ & Poirier, L (1996) Ethanol feeding of micropigs alters methionine metabolism and increases hepatocellular apoptosis and proliferation. Hepatology 23, 497–505.CrossRefGoogle ScholarPubMed
Harty, LC, Caporaso, NE, Hayes, RB, Winn, DM, Bravo-Otero, E, Blot, WJ, Kleinman, DV, Brown, LM, Armenian, HK, Fraumeni, JF Jr & Shields, PG (1997) Alcohol dehydrogenase 3 genotype and risk of oral cavity and pharyngeal cancers. Journal of the National Cancer Institute 89, 1698–1705.Google Scholar
Helander, A & Lindahl-Kiessling, K (1991) Increased frequency of acetaldehyde-induced sister-chromatide exchanges in human lymphocytes treated with an aldehyde dehydrogenase inhibitor. Mutatation Research 264, 103–107.Google Scholar
Homann, N, Jousimies-Somer, H, Jokelainen, K, Heine, R & Salaspuro, M (1997a) High acetaldehyde levels in saliva after ethanol consumption: Methodological aspects and pathogenetic implications. Carcinogenesis 18, 1739–1743.CrossRefGoogle ScholarPubMed
Homann, N, Karkkainen, P, Koivisto, T, Nosova, T, Jokelainen, K & Salaspuro, M (1997b) Effects of acetaldehyde on cell regeneration and differentiation of the upper gastrointestinal tract mucosa. Journal of the National Cancer Institute 89, 1692–1697.CrossRefGoogle ScholarPubMed
Homann, N, Tillonen, J, Meurman, JH, Rintamaki, H, Lindqvist, C, Rautio, M, Jousimies-Somer, H & Salaspuro, M (2000) Increased salivary acetaldehyde levels in heavy drinkers and smokers: A microbiological approach to oral cavity cancer. Carcinogenesis 21, 663–668.Google Scholar
Homann, N, Tillonen, J, Rintamaki, H, Salaspuro, M, Lindqvist, C & Meurman, JH (2001) Poor dental status increases the acetaldehyde production from ethanol in saliva. A possible link to the higher risk of oral cancer among alcohol consumers. Oral Oncology 37, 153–158.Google Scholar
Hui, AM & Makuuchi, M (1999) Molecular basis of multistep hepatocarcinogenesis: genetic and epigenetic events. Scandinavian Journal of Gastroenterology 8, 737–742.Google Scholar
Iwata, N, Yamamoto, H, Sasaki, S, Itoh, F, Suzuki, H, Kikuchi, T et al. (2000) Frequent hypermethylation of CpG islands and loss of expression of the 14–3-3 sigma gene in human hepatocellular carcinoma. Oncogene 19, 5298–5302.CrossRefGoogle ScholarPubMed
Jokelainen, K, Heikkonen, E, Roine, R, Lehtonen, H & Salaspuro, M (1996) Increased acetaldehyde production by mouthwashings from patients with oral cavity, laryngeal, or pharyngeal cancer. Alcohol, Clinical and Experimental Research 20, 1206–1210.Google Scholar
Kanai, Y, Hui, AM, Sun, L, Ushijima, S, Sakamoto, M, Tsuda, H & Hirohashi, S (1999) DNA hypermethylation at the D17S5 locus and reduced HIC-1 mRNA expression are associated with hepatocarcinogenesis. Hepatology 29, 703–709.Google Scholar
Kanai, Y, Ushijima, S, Tsuda, H, Sakamoto, M & Hirohashi, S (2000) Aberrant DNA methylation precedes loss of heterozygosity on chromosome 16 in chronic hepatitis and liver cirrhosis. Cancer Letters 148, 73–80.CrossRefGoogle ScholarPubMed
Kondo, Y, Kanai, Y, Sakamoto, M, Mizokami, M, Ueda, R & Hirohashi, S (2000) 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 32, 970–979.Google Scholar
Labadarios, D, Rossouw, JE McConnell, JB Davis, M & Williams, R (1977) Vitamin B6 deficiency in chronic liver disease – evidence for increased degradation of pyridoxal-5'-phosphate. Gut 18, 23–27.Google Scholar
Leo, MA, Kim, C & Lieber, CS (1986) Increased vitamin A in esophagus and other extrahepatic tissues after chronic ethanol consumption in the rat. Alcohol, Clinical and Experimental Research 10, 487–492.Google Scholar
Leo, MA & Lieber, CS (1982) Hepatic vitamin A depletion in alcoholic liver injury. New England Journal of Medicine 307, 597–601.Google Scholar
Li, JJ, Benesova, M, Goette, K, Fiehn, W, Conradt, C, Hoermann, K, Salaspuro, M & Seitz, HK (2001) Enhanced risk of upper alimentary tract cancer in patients with the alcohol dehydrogenase 3*1 allele due to increased salivary acetaldehyde following ethanol ingestion. Gastroenterology 120 A-160.Google Scholar
Lieber, CS (1994a) Mechanisms of ethanol-drug nutrition interactions. Journal of Toxicology Clinical Toxicology 32, 631–681.Google Scholar
Lieber, CS (1994b) Alcohol and the liver: 1994 update. Gastroenterology 106, 1085–1105.CrossRefGoogle ScholarPubMed
Lieber, CS, Casini, A DeCarli, LM Kim, CI, Lowe, N, Sasaki, R & Leo, MA (1990) S -adenosyl-L-methionine attenuates alcohol-induced liver injury in the baboon. Hepatology 11, 165–172.Google Scholar
Lippman, SM & Lotan, R (2000) Advances in the development of retinoids as chemopreventive agents. Journal of Nutrition 130, 479S–482S.CrossRefGoogle ScholarPubMed
Liu, C, Chung, J, Seitz, HK, Russell, RM & Wang, XD (2002) Chlormethiazole treatment prevents reduced hepatic vitamin A levels in alcohol-fed rats. Alcohol, Clinical and Experimental Research 26, 1703–1709.Google Scholar
Liu, C, Russell, RM, Seitz, HK & Wang, XD (2001) Ethanol enhances retinoic acid metabolism into polar metabolites in rat liver via induction of cytochrome P450 2E1. Gastroenterology 120, 179–189.CrossRefGoogle Scholar
Lumeng, L & Li, TK (1974) Vitamin B6 metabolism in chronic alcohol abuse. Journal of Clinical Investigations 53, 693–704.Google Scholar
Maier, H, Born, IA, Veith, S, Adler, D & Seitz, HK (1986) The effect of chronic ethanol consumption on salivary gland morphology and function in the rat. Alcohol, Clinical and Experimental Research 10, 425–427.CrossRefGoogle ScholarPubMed
Matsuda, T, Terashima, I, Matsumoto, Y, Yabushita, H, Matsui, S & Shibutani, S (1999) Effective utilization of N2-ethyl-2'-deoxyguanosine triphosphate during DNA synthesis catalyzed by mammalian replicative DNA polymerases. Biochemistry 38, 929–935.Google Scholar
Miyakawa, H, Liu, J, Noguchi, O, Marumo, F & Sato, C (1996) Effect of alcohol drinking on gene expression of hepatic O 6 -methylguanine DNA methyltransferase in chronic liver diseases. Alcohol, Clinical and Experimental Research 20, 297A–300A.Google Scholar
Mobarhan, S, Seitz, HK, Russell, RM, Mehta, R, Hupert, J, Friedman, H, Layden, TJ, Meydani, M & Langenberg, P (1991) Age-related effects of chronic ethanol intake on vitamin A status in Fisher 344 rats. Journal of Nutrition 121, 510–517.Google Scholar
Olshan, AF, Weissler, MC, Watson, MA & Bell, DA (2001) Risk of head and neck cancer and the alcohol dehydrogenase 3 genotype. Carcinogenesis 22, 57–61.Google Scholar
Oneta, CM, Lieber, CS, Li, J, Ruttimann, S, Schmid, B, Lattmann, J, Rosman, AS & Seitz, HK (2002) Dynamics of cytochrome P450 2E1 activity in man: induction by ethanol and disappearance during withdrawal phase. Journal of Hepatology 36, 47–52.CrossRefGoogle ScholarPubMed
Pogribny, IP, Basnakian, AG, Miller, BJ, Lopatina, NG, Poirier, LA & James, SJ (1995) Breaks in genomic DNA and within the p53 gene are associated with hypomethylation in livers of folate/methyl-deficient rats. Cancer Research 55, 1894–1901.Google Scholar
Salaspuro, MP (2003) Acetaldehyde, microbes, and cancer of the digestive tract. Critical Reviews in Clinical Laboratory Science 40, 183–208.Google Scholar
Sato, M & Lieber, CS (1982) Increased metabolism of retinoic acid after chronic ethanol consumption in rat liver microsomes. Archives of Biochemistry and Biophysics 213, 557–564.Google Scholar
Savage, D & Lindenbaum, J (1986) Anemia in alcoholics. Medicine 56, 322–328.Google Scholar
Seitz, HK, Matsuzaki, S, Yokoyama, A, Homann, N, Vakevainen, S & Wang, XD (2001) Alcohol and cancer. Alcohol, Clinical and Experimental Research 25, 137–143.Google Scholar
Seitz, HK & Oneta, CM (1998) Gastrointestinal alcohol dehydrogenases. Nutrition Reviews 56, 52–60.Google Scholar
Seitz, HK & Oswald, BR (1992) Effect of ethanol on procarcinogen activation. In Alcohol and Cancer, pp55 – 72 [Watson, RReditor]. Boca Raton, FL CRC PressGoogle Scholar
Seitz, HK, Pöschl, G & Simanowski, UA (1998) Alcohol and cancer. Recent Developments in Alcoholism 14, 67–95.Google Scholar
Shen, L, Fang, J, Qiu, D, Zhang, T, Yang, J, Chen, S & Xiao, S (1998) Correlation between DNA methylation and pathological changes in human hepatocellular carcinoma. Hepatogastroenterology 45, 1753–1759.Google Scholar
Shimizu, M, Lasker, JM, Tsutsumi, M & Lieber, CS (1990) Immunohistochemical localization of ethanol-inducible P450 2E1 in the rat alimentary tract. Gastroenterology 99, 1044–1053.Google Scholar
Simanowski, UA, Suter, P, Stickel, F, Maier, H, Waldherr, R, Smith, D, Russell, RM & Seitz, HK (1993) Esophageal epithelial hyperregeneration following chronic ethanol ingestion: Effect of age and salivary gland function. Journal of the National Cancer Institute 85, 2030–2033.Google Scholar
Simoni, D, Tolomeo, M (2001) Retinoids, apoptosis and cancer. Current Pharmaceutical Design 7, 1823–1837.Google Scholar
Speisky, H MacDonald, A Giles, G, Orrego, H & Israel, Y (1985) Increased loss and decreased synthesis of hepatic glutathione after acute ethanol administration. Turnover studies. Biochemical Journal 225, 565–572.CrossRefGoogle ScholarPubMed
Stickel, F, Choi, SW, Kim, YI, Bagley, PJ, Seitz, HK, Russell, RM, Selhub, J & Mason, JB (2000) Effect of chronic alcohol consumption on total plasma homocysteine level in rats. Alcohol, Clinical and Experimental Research 24, 259–264.CrossRefGoogle ScholarPubMed
Stickel, F, Homann, N, Benesova, M, Jacobs, A, Schuppan, D, Hahn, EG, Conradt, C, Ludwig, D, Zuber, I, Blum, HE & Seitz, HK (2003) Genetic predisposition for alcohol associated upper aerodigestive tract cancer and hepatocellular cancer in heavy drinkers with the alcohol dehydrogenase 3*1 allele. Gastroenterology 124 A547Google Scholar
Sturgis, EM, Dahlstrom, KR, Guan, Y, Eicher, SA, Strom, SS, Spitz, MR & Wei, Q (2001) Alcohol dehydrogenase 3 genotype is not associated with risk of squamous cell carcinoma of the oral cavity and pharynx. Cancer Epidemiology, Biomarkers and Prevention 10, 273–275.Google Scholar
Trimble, KC, Molloy, AM, Scott, JM & Weir, DG (1993) The effect of ethanol on one-carbon metabolism: increased methionine catabolism and lipotrope methyl-group wastage. Hepatology 18, 984–989.Google Scholar
Uto, H, Ido, A, Moriuchi, A, Onaga, Y, Nagata, K, Onaga, M, Tahara, Y, Hori, T, Hirono, S, Hayashi, K & Tsubouchi, H (2001) Transduction of antisense cyclin D1 using two-step gene transfer inhibits the growth of rat hepatoma cells. Cancer Research 61, 4779–4783.Google Scholar
Vakevainen, S, Tillonen, J, Agarwal, DP, Srivastava, N & Salaspuro, M (2000) High salivary acetaldehyde after a moderate dose of alcohol in ALDH2-deficient subjects: strong evidence for the local carcinogenic action of acetaldehyde. Alcohol, Clinical and Experimental Research 24, 873–877.Google Scholar
Wainfan, E, Dizik, M, Stender, M & Christman, JK (1989) Rapid appearance of hypomethylated DNA in livers of rats fed cancer-promoting, methyl-deficient diets. Cancer Research 49, 4094–4097.Google ScholarPubMed
Wang, XD (2001) Retinoids and alcoholic liver disease Alcohol in Health and Disease 427 – 452 Agarwal, DP, Seitz, HK, New York: Marcel Dekker.Google Scholar
Wang, XD, Liu, C, Chung, J, Stickel, F, Seitz, HK & Russell, RM (1998) Chronic alcohol intake reduces retinoic acid concentration and enhances AP-1 (c-JUN and c-FOS) expression in rat liver. Hepatology 28, 744–750.Google Scholar
Woutersen, RA, Appelman, LM, Van Garderen-Hoetmer, A & Feron, VJ (1986) Inhalation toxicity of acetaldehyde in rats: III. Carcinogenicity study. Toxicology 41, 213–231.Google Scholar
Yokoyama, A, Muramatsu, T, Ohmori, T, Makuuchi, H, Higuchi, S, Matsushita, S, Yoshino, K, Maruyama, K, Nakano, M & Ishii, H (1996) Multiple primary esophageal and concurrent aerodigestive tract cancer and the aldehyde dehydrogenase-2 genotype of Japanese alcoholics. Cancer 77, 1986–1990.Google Scholar
Yokoyama, A, Muramatsu, T & Ohmori, T (1998) Alcohol related cancers and aldehyde dehydrogenase in Japanese alcoholics. Carcinogenesis 19, 1383–1387.Google Scholar
Yokoyama, A, Muramatsu, T, Omori, T, Matsushita, S, Yoshimizu, H, Higuchi, S, Yokoyama, T, Maruyama, K & Ishii, H (1999) Alcohol and aldehyde gene polymorphisms influence susceptibility to esophageal cancer in Japanese alcoholics. Alcohol, Clinical and Experimental Research 23, 1705–1710.Google Scholar
Young, MR, Li, JJ, Rincon, M, Flavell, RA, Sathyanarayana, BK, Hunziker, R & Colburn, N (1999) Transgenic mice demonstrate AP-1 (activator protein 1) transactivation is required for tumor promotion. Proceedings of the National Academy of Sciences USA 96, 9827–9832.Google Scholar
Zapisek, WF & Cronin, GM Lyn-Cook, BD Poirier, LA (1992) The onset of oncogene hypomethylation in the livers of rats fed methyl-deficient, amino acid-defined diets. Carcinogenesis 13, 1869–1872.Google Scholar