title: Effects of ALDH2 genotype, PPI treatment and L-cysteine on carcinogenic acetaldehyde in gastric juice and saliva after intragastric alcohol administration.
abstract: Acetaldehyde (ACH) associated with alcoholic beverages is Group 1 carcinogen to humans (IARC/WHO). Aldehyde dehydrogenase (ALDH2), a major ACH eliminating enzyme, is genetically deficient in 30-50% of Eastern Asians. In alcohol drinkers, ALDH2-deficiency is a well-known risk factor for upper aerodigestive tract cancers, i.e., head and neck cancer and esophageal cancer. However, there is only a limited evidence for stomach cancer. In this study we demonstrated for the first time that ALDH2 deficiency results in markedly increased exposure of the gastric mucosa to acetaldehyde after intragastric administration of alcohol. Our finding provides concrete evidence for a causal relationship between acetaldehyde and gastric carcinogenesis. A plausible explanation is the gastric first pass metabolism of ethanol. The gastric mucosa expresses alcohol dehydrogenase (ADH) enzymes catalyzing the oxidation of ethanol to acetaldehyde, especially at the high ethanol concentrations prevailing in the stomach after the consumption of alcoholic beverages. The gastric mucosa also possesses the acetaldehyde-eliminating ALDH2 enzyme. Due to decreased mucosal ALDH2 activity, the elimination of ethanol-derived acetaldehyde is decreased, which results in its accumulation in the gastric juice. We also demonstrate that ALDH2 deficiency, proton pump inhibitor (PPI) treatment, and L-cysteine cause independent changes in gastric juice and salivary acetaldehyde levels, indicating that intragastric acetaldehyde is locally regulated by gastric mucosal ADH and ALDH2 enzymes, and by oral microbes colonizing an achlorhydric stomach. Markedly elevated acetaldehyde levels were also found at low intragastric ethanol concentrations corresponding to the ethanol levels of many foodstuffs, beverages, and dairy products produced by fermentation. A capsule that slowly releases L-cysteine effectively eliminated acetaldehyde from the gastric juice of PPI-treated ALDH2-active and ALDH2-deficient subjects. These results provide entirely novel perspectives for the prevention of gastric cancer, especially in established risk groups.
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Ryuhei
authors.initials: R
authors.lastname: Maejima
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Iijima
authors.affiliation: Research Unit on Acetaldehyde and Cancer, University of Helsinki, Helsinki, Finland.
authors.forename: Pertti
authors.initials: P
authors.lastname: Kaihovaara
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Waku
authors.initials: W
authors.lastname: Hatta
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Koike
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Imatani
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Tooru
authors.initials: T
authors.lastname: Shimosegawa
authors.affiliation: Research Unit on Acetaldehyde and Cancer, University of Helsinki, Helsinki, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Salaspuro
mesh_terms: D000079:Acetaldehyde / Q000032:analysis / Q000378:metabolism* / Q000633:toxicity; D000328:Adult; D000428:Alcohol Drinking; D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D002273:Carcinogens / Q000032:analysis / Q000378:metabolism* / Q000633:toxicity; D003545:Cysteine / Q000494:pharmacology*; D000431:Ethanol / Q000032:analysis / Q000378:metabolism; D005750:Gastric Juice / Q000378:metabolism*; D005753:Gastric Mucosa / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D005838:Genotype; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D054328:Proton Pump Inhibitors / Q000008:administration & dosage*; D012463:Saliva / Q000378:metabolism*
chemical_list: D002273:Carcinogens; D054328:Proton Pump Inhibitors; D000431:Ethanol; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000079:Acetaldehyde; D003545:Cysteine
references.citation: Nucleic Acids Res. 2005 Jun 21;33(11):3513-20
references.pmid: 15972793
references.citation: Carcinogenesis. 2013 Jul;34(7):1510-5
references.pmid: 23455379
references.citation: Blutalkohol. 1994 Mar;31(2):76-9
references.pmid: 8204224
references.citation: Alcohol Clin Exp Res. 2011 Mar;35(3):516-22
references.pmid: 21143248
references.citation: Alcohol Clin Exp Res. 2000 Jun;24(6):873-7
references.pmid: 10888077
references.citation: J Gastroenterol Hepatol. 2007 Feb;22(2):210-7
references.pmid: 17295873
references.citation: Proc Nutr Soc. 2004 Feb;63(1):49-63
references.pmid: 15099407
references.citation: World J Gastroenterol. 2013 Apr 28;19(16):2560-8
references.pmid: 23674860
references.citation: Int J Cancer. 2008 Mar 15;122(6):1347-56
references.pmid: 18033686
references.citation: Cancer Epidemiol Biomarkers Prev. 2000 Oct;9(10):1051-8
references.pmid: 11045787
references.citation: Int J Cancer. 2002 Jan 20;97(3):361-4
references.pmid: 11774289
references.citation: Alcohol. 1996 May-Jun;13(3):257-62
references.pmid: 8734840
references.citation: Int J Cancer. 1985 Feb 15;35(2):173-7
references.pmid: 3871738
references.citation: Pharmacol Biochem Behav. 1980;13 Suppl 1:119-24
references.pmid: 7243824
references.citation: Alcohol Clin Exp Res. 2001 Jun;25(6):829-34
references.pmid: 11410717
references.citation: World J Gastroenterol. 2010 Sep 7;16(33):4210-20
references.pmid: 20806441
references.citation: Int J Epidemiol. 2011 Aug;40(4):1047-55
references.pmid: 21507992
references.citation: Keio J Med. 2010;59(4):115-30
references.pmid: 21187698
references.citation: Cancer Epidemiol Biomarkers Prev. 2006 Jan;15(1):146-9
references.pmid: 16434601
references.citation: Am J Gastroenterol. 2011 Nov;106(11):1923-9
references.pmid: 21931379
references.citation: J Am Coll Nutr. 2012 Oct;31(5):375-84
references.pmid: 23529995
references.citation: Carcinogenesis. 1997 Sep;18(9):1739-43
references.pmid: 9328169
references.citation: Dig Dis Sci. 2010 May;55(5):1349-55
references.pmid: 19513836
references.citation: IARC Monogr Eval Carcinog Risks Hum. 2012;100(Pt E):1-538
references.pmid: 23193840
references.citation: Gastroenterology. 1997 Mar;112(3):766-75
references.pmid: 9041238
references.citation: Ann Hum Genet. 2009 May;73(Pt 3):335-45
references.pmid: 19456322
references.citation: Agents Actions. 1975 May;5(2):164-73
references.pmid: 1171591
references.citation: Scand J Gastroenterol. 2002 Jun;37(6):648-55
references.pmid: 12126241
references.citation: PLoS Med. 2009 Mar 24;6(3):e50
references.pmid: 19320537
references.citation: PLoS One. 2014 Mar 14;9(3):e88779
references.pmid: 24633362
references.citation: J Dig Dis. 2011 Apr;12(2):51-9
references.pmid: 21401890
references.citation: Life Sci. 1992;51(17):1333-7
references.pmid: 1406052
references.citation: Genes Nutr. 2010 Jun;5(2):121-8
references.pmid: 19847467
references.citation: Scand J Gastroenterol. 2009;44(8):912-25
references.pmid: 19396661
references.citation: PLoS One. 2013 Sep 13;8(9):e74418
references.pmid: 24058561
references.citation: Int J Cancer. 2004 Sep 10;111(4):480-3
references.pmid: 15239123
references.citation: Cancer Epidemiol Biomarkers Prev. 2013 Jan;22(1):69-75
references.pmid: 23155139
references.citation: Asian Pac J Cancer Prev. 2010;11(4):1073-7
references.pmid: 21133627
references.citation: Alcohol Res. 2012;34(3):339-44
references.pmid: 23134050
references.citation: Ann Oncol. 2012 Jan;23(1):28-36
references.pmid: 21536659
references.citation: Int J Cancer. 2003 Nov 20;107(4):629-34
references.pmid: 14520702
references.citation: Scand J Gastroenterol. 2010 Nov;45(11):1338-44
references.pmid: 20521872
references.citation: Alcohol Clin Exp Res. 2006 Jul;30(7):1132-42
references.pmid: 16792560
references.citation: Aliment Pharmacol Ther. 2000 Nov;14(11):1511-8
references.pmid: 11069323
references.citation: World J Gastroenterol. 2001 Dec;7(6):801-4
references.pmid: 11854905
references.citation: Alcohol Clin Exp Res. 2008 Sep;32(9):1607-14
references.pmid: 18616675
references.citation: World J Gastroenterol. 2005 Jun 7;11(21):3175-81
references.pmid: 15929164
references.citation: Mutat Res. 2009 Feb 19;673(1):74-7
references.pmid: 19101651
references.citation: Oral Oncol. 2007 Feb;43(2):181-6
references.pmid: 16859955