Role of Chronic Alcoholism Causing Cancer in Omnivores and Vegetarians through Epigenetic Modifications

Abstract

One of the significant consequences of alcohol consumption is cancer formation via several contributing factors such as action of alcohol metabolites, vitamin deficiencies, and oxidative stress. All these factors have been shown to cause epigenetic modifications via DNA hypomethylation, thus forming a basis for cancer development. Several published reviews and studies were systematically reviewed. Omnivores and vegetarians differ in terms of nutritional intake and deficiencies. As folate deficiency was found to be common among the omnivores, chronic alcoholism could possibly cause damage and eventually cancer in an omnivorous individual via DNA hypomethylation due to folate deficiency. Furthermore, as niacin was found to be deficient among vegetarians, damage in vegetarian chronic alcoholics could be due to increased NADH/NAD⁺ ratio, thus slowing alcohol metabolism in liver leading to increased alcohol and acetaldehyde which inhibit methyltransferase enzymes, eventually leading to DNA hypomethylation. Hence correcting the concerned deficiency and supplementation with S-adenosyl methionine could prove to be protective in chronic alcohol use.

Keywords

chronic alcohol use / cancer epigenetic mechanisms / dietary deficiencies / epigenetic modifications / omnivores and vegetarians

References

[1] Boffetta P, Hashibe M, La Vecchia C, Zatonski W, Rehm J. The burden of cancer attributable to alcohol drinking. Int J Cancer 2006; 119(04): 884-887

[2] Zakhari S. Alcohol metabolism and epigenetic changes. Alcohol Res 2013; 35(01): 6-16

[3] Ulrey CL, Liu L, Andrews LG, Tollefsbol TO. The impact of metabolism on DNA methylation. Hum Mol Genet 2005; 14(01): R139-R147

[4] Varela-Rey M, Woodhoo A, Martinez-Chantar ML, Mato JM, Lu SC. Alcohol, DNA methylation, and cancer. Alcohol Res 2013; 35(01): 25-35

[5] Grillo MA, Colombatto S. S-adenosylmethionine and its products. Amino Acids 2008; 34(02): 187-193

[6] Seitz HK, Stickel F. Molecular mechanisms of alcohol-mediated carcinogenesis. Nat Rev Cancer 2007; 7(08): 599-612

[7] Barak AJ, Beckenhauer HC, Tuma DJ, Badakhsh S. Effects of prolonged ethanol feeding on methionine metabolism in rat liver. Biochem Cell Biol 1987; 65(03): 230-233

[8] Esfandiari F, Medici V, Wong DH, et al. Epigenetic regulation of hepatic endoplasmic reticulum stress pathways in the ethanol-fed cystathionine beta synthase-deficient mouse. Hepatology 2010; 51(03): 932-941

[9] Garro AJ, McBeth DL, Lima V, Lieber CS. Ethanol consumption inhibits fetal DNA methylation in mice: implications for the fetal alcohol syndrome. Alcohol Clin Exp Res 1991; 15(03): 395-398

[10] Bielawski DM, Zaher FM, Svinarich DM, Abel EL. Paternal alcohol exposure affects sperm cytosine methyltransferase messenger RNA levels. Alcohol Clin Exp Res 2002; 26(03): 347-351

[11] Bönsch D, Lenz B, Fiszer R, Frieling H, Kornhuber J, Bleich S. Lowered DNA methyltransferase (DNMT-3b) mRNA expression is associated with genomic DNA hypermethylation in patients with chronic alcoholism. J Neural Transm (Vienna) 2006; 113(09): 1299-1304

[12] Cunningham CC, Bailey SM. Ethanol consumption and liver mitochondria function. Biol Signals Recept 2001; 10(3-4): 271-282

[13] Bardag-Gorce F, French BA, Nan L, et al. CYP2E1 induced by ethanol causes oxidative stress, proteasome inhibition and cytokeratin aggresome (Mallory body-like) formation. Exp Mol Pathol 2006; 81(03): 191-201

[14] Weitzman SA, Turk PW, Milkowski DH, Kozlowski K. Free radical adducts induce alterations in DNA cytosine methylation. Proc Natl Acad Sci U S A 1994; 91(04): 1261-1264

[15] French SW. Epigenetic events in liver cancer resulting from alcoholic liver disease. Alcohol Res 2013; 35(01): 57-67

[16] Halsted CH. Nutrition and alcoholic liver disease. Semin Liver Dis 2004; 24(03): 289-304

[17] Halsted CH, Robles EA, Mezey E. Decreased jejunal uptake of labeled folic acid ( 3 H-PGA) in alcoholic patients: roles of alcohol and nutrition. N Engl J Med 1971; 285(13): 701-706

[18] Halsted CH, Griggs RC, Harris JW. The effect of alcoholism on the absorption of folic acid (H3-PGA) evaluated by plasma levels and urine excretion. J Lab Clin Med 1967; 69(01): 116-131

[19] Villanueva JA, Devlin AM, Halsted CH. Reduced folate carrier: tissue distribution and effects of chronic ethanol intake in the micropig. Alcohol Clin Exp Res 2001; 25(03): 415-420

[20] Wani NA, Kaur J. Reduced levels of folate transporters (PCFT and RFC) in membrane lipid rafts result in colonic folate malabsorption in chronic alcoholism. J Cell Physiol 2011; 226(03): 579-587

[21] Wani NA, Hamid A, Kaur J. Alcohol-associated folate disturbances result in altered methylation of folate-regulating genes. Mol Cell Biochem 2012; 363(1-2): 157-166

[22] Russell RM, Rosenberg IH, Wilson PD, et al. Increased urinary excretion and prolonged turnover time of folic acid during ethanol ingestion. Am J Clin Nutr 1983; 38(01): 64-70

[23] McMartin KE, Collins TD, Eisenga BH, Fortney T, Bates WR, Bairnsfather L. Effects of chronic ethanol and diet treatment on urinary folate excretion and development of folate deficiency in the rat. J Nutr 1989; 119(10): 1490-1497

[24] Tamura T, Halsted CH. Folate turnover in chronically alcoholic monkeys. J Lab Clin Med 1983; 101(04): 623-628

[25] Lu SC. S-Adenosylmethionine. Int J Biochem Cell Biol 2000; 32(04): 391-395

[26] Baan R, Straif K, Grosse Y, et al; WHO International Agency for Research on Cancer Monograph Working Group. Carcinogenicity of alcoholic beverages. Lancet Oncol 2007; 8(04): 292-293

[27] Donato F, Tagger A, Gelatti U, et al. Alcohol and hepatocellular carcinoma: the effect of lifetime intake and hepatitis virus infections in men and women. Am J Epidemiol 2002; 155(04): 323-331

[28] Morgan TR, Mandayam S, Jamal MM. Alcohol and hepatocellular carcinoma. Gastroenterology2004; 127 (05) (Suppl. 01) S87-S96

[29] Bardag-Gorce F, Oliva J, Dedes J, Li J, French BA, French SW. Chronic ethanol feeding alters hepatocyte memory which is not altered by acute feeding. Alcohol Clin Exp Res 2009; 33(04): 684-692

[30] Calvisi DF, Ladu S, Gorden A, et al. Mechanistic and prognostic significance of aberrant methylation in the molecular pathogenesis of human hepatocellular carcinoma. J Clin Invest 2007; 117(09): 2713-2722

[31] Hernandez-Vargas H, Lambert MP, Le Calvez-Kelm F, et al. Hepatocellular carcinoma displays distinct DNA methylation signatures with potential as clinical predictors. PLoS One 2010; 5(03): e9749

[32] Medici V, Halsted CH. Folate, alcohol, and liver disease. Mol Nutr Food Res 2013; 57(04): 596-606

[33] Bardag-Gorce F, French BA, Joyce M, et al. Histone acetyltransferase p300 modulates gene expression in an epigenetic manner at high blood alcohol levels. Exp Mol Pathol 2007; 82(02): 197-202

[34] Zampetaki A, Xiao Q, Zeng L, Hu Y, Xu Q. TLR4 expression in mouse embryonic stem cells and in stem cell-derived vascular cells is regulated by epigenetic modifications. Biochem Biophys Res Commun 2006; 347(01): 89-99

[35] Bardag-Gorce F, Oliva J, Lin A, Li J, French BA, French SW. SAMe prevents the up regulation of toll-like receptor signaling in Mallory-Denk body forming hepatocytes. Exp Mol Pathol 2010; 88(03): 376-379

[36] Oliva J, French SW. Changes in IL12A methylation pattern in livers from mice fed DDC. Exp Mol Pathol 2012; 92(02): 191-193

[37] Schüpbach R, Wegmüller R, Berguerand C, Bui M, Herter-Aeberli I. Micronutrient status and intake in omnivores, vegetarians and vegans in Switzerland. Eur J Nutr 2017; 56(01): 283-293

[38] 38 Farmer B. “Comparison of Nutrient Intakes for Vegetarians, Non-Vegetarians, and Dieters: Results from the National Health and Nutrition Examination Survey 1999-2004.” [Master's Theses and Doctoral Dissertations]. Dietetics and Clinical Nutrition Commons. 2009; 150

[39] Giovannucci E, Rimm EB, Ascherio A, Stampfer MJ, Colditz GA, Willett WC. Alcohol, low-methionine-low-folate diets, and risk of colon cancer in men. J Natl Cancer Inst 1995; 87(04): 265-273

[40] van Engeland M, Weijenberg MP, Roemen GM, et al. Effects of dietary folate and alcohol intake on promoter methylation in sporadic colorectal cancer: the Netherlands cohort study on diet and cancer. Cancer Res 2003; 63(12): 3133-3137

[41] Kim J, Cho YA, Kim DH, et al. Dietary intake of folate and alcohol, MTHFR C677T polymorphism, and colorectal cancer risk in Korea. Am J Clin Nutr 2012; 95(02): 405-412

[42] Pelucchi C, Tramacere I, Boffetta P, Negri E, La Vecchia C. Alcohol consumption and cancer risk. Nutr Cancer 2011; 63(07): 983-990

[43] Seitz HK, Pelucchi C, Bagnardi V, La Vecchia C. Epidemiology and pathophysiology of alcohol and breast cancer: Update 2012. Alcohol Alcohol 2012; 47(03): 204-212

[44] Larsson SC, Rafter J, Holmberg L, Bergkvist L, Wolk A. Red meat consumption and risk of cancers of the proximal colon, distal colon and rectum: the Swedish Mammography Cohort. Int J Cancer 2005; 113(05): 829-834

[45] English DR, MacInnis RJ, Hodge AM, Hopper JL, Haydon AM, Giles GG. Red meat, chicken, and fish consumption and risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev 2004; 13(09): 1509-1514

[46] Norat T, Bingham S, Ferrari P, et al. Meat, fish, and colorectal cancer risk: the European Prospective Investigation into cancer and nutrition. J Natl Cancer Inst 2005; 97(12): 906-916

[47] Chan DS, Lau R, Aune D, et al. Red and processed meat and colorectal cancer incidence: meta-analysis of prospective studies. PLoS One 2011; 6(06): e20456

[48] Bouvard V, Loomis D, Guyton KZ, et al; International Agency for Research on Cancer Monograph Working Group. Carcinogenicity of consumption of red and processed meat. Lancet Oncol 2015; 16(16): 1599-1600

[49] Kirkland JB. Niacin and carcinogenesis. Nutr Cancer 2003; 46(02): 110-118

[50] Takahashi S, Nakae D, Yokose Y, et al. Enhancement of DEN initiation of liver carcinogenesis by inhibitors of NAD+ ADP ribosyl transferase in rats. Carcinogenesis 1984; 5(07): 901-906

[51] Tummala KS, Gomes AL, Yilmaz M, et al. Inhibition of de novo NAD(+) synthesis by oncogenic URI causes liver tumorigenesis through DNA damage. Cancer Cell 2014; 26(06): 826-839

[52] Christensen BC, Kelsey KT, Zheng S, et al. Breast cancer DNA methylation profiles are associated with tumor size and alcohol and folate intake. PLoS Genet 2010; 6(07): e1001043

[53] Hirakawa N, Okauchi R, Miura Y, Yagasaki K. Anti-invasive activity of niacin and trigonelline against cancer cells. Biosci Biotechnol Biochem 2005; 69(03): 653-658

[54] Esfandiari F, You M, Villanueva JA, Wong DH, French SW, Halsted CH. S-adenosylmethionine attenuates hepatic lipid synthesis in micropigs fed ethanol with a folate-deficient diet. Alcohol Clin Exp Res 2007; 31(07): 1231-1239

[55] Villanueva JA, Esfandiari F, White ME, Devaraj S, French SW, Halsted CH. S-adenosylmethionine attenuates oxidative liver injury in micropigs fed ethanol with a folate-deficient diet. Alcohol Clin Exp Res 2007; 31(11): 1934-1943

[56] Medici V, Virata MC, Peerson JM, et al. S-adenosyl-L-methionine treatment for alcoholic liver disease: a double-blinded, randomized, placebo-controlled trial. Alcohol Clin Exp Res 2011; 35(11): 1960-1965

[57] Kharbanda KK, Mailliard ME, Baldwin CR, Beckenhauer HC, Sorrell MF, Tuma DJ. Betaine attenuates alcoholic steatosis by restoring phosphatidylcholine generation via the phosphatidylethanolamine methyltransferase pathway. J Hepatol 2007; 46 (02) 314-321 58 Li J, Li XM, Caudill M, et al. Betaine feeding prevents the blood alcohol cycle in rats fed alcohol continuously for 1 month using the rat intragastric tube feeding model. Exp Mol Pathol 2011; 91(02): 540-547

[59] Shi QZ, Wang LW, Zhang W, Gong ZJ. Betaine inhibits toll-like receptor 4 expression in rats with ethanol-induced liver injury. World J Gastroenterol 2010; 16(07): 897-903

[60] Kharbanda KK, Rogers II DD, Mailliard ME, et al. Role of elevated S-adenosylhomocysteine in rat hepatocyte apoptosis: protection by betaine. Biochem Pharmacol 2005; 70(12): 1883-1890

RIGHTS & PERMISSIONS

2020 Global Medical Genetics