Effects of ALDH2 genotype, PPI treatment and L-cysteine on carcinogenic acetaldehyde in gastric juice and saliva after intragastric alcohol administration
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 aerodig...
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| creator | Maejima, Ryuhei Iijima, Katsunori Kaihovaara, Pertti Hatta, Waku Koike, Tomoyuki Imatani, Akira Shimosegawa, Tooru Salaspuro, Mikko |
| description | 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. |
| doi_str_mv | 10.1371/journal.pone.0120397 |
| format | Article |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0120397</identifier><identifier>PMID: 25831092</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acetaldehyde ; Acetaldehyde - analysis ; Acetaldehyde - metabolism ; Acetaldehyde - toxicity ; Adult ; Alcohol dehydrogenase ; Alcohol Drinking ; Alcohol use ; Alcoholic beverages ; Aldehyde dehydrogenase ; Aldehyde Dehydrogenase - genetics ; Aldehyde Dehydrogenase, Mitochondrial ; Beverage industry ; Beverages ; Cancer ; Carcinogenesis ; Carcinogens ; Carcinogens - analysis ; Carcinogens - metabolism ; Carcinogens - toxicity ; Cysteine ; Cysteine - pharmacology ; Cystine ; Dairy products ; Dehydrogenase ; Enzymes ; Esophageal cancer ; Esophagus ; Ethanol ; Ethanol - analysis ; Ethanol - metabolism ; Fermentation ; Gastric cancer ; Gastric juice ; Gastric Juice - metabolism ; Gastric mucosa ; Gastric Mucosa - drug effects ; Gastric Mucosa - enzymology ; Gastric Mucosa - metabolism ; Genetic aspects ; Genotype ; Head ; Head & neck cancer ; Head and neck cancer ; Health risks ; Helicobacter pylori ; Humans ; Hydrogen-Ion Concentration ; Male ; Metabolism ; Oxidation ; Physiological aspects ; Proton pump inhibitors ; Proton Pump Inhibitors - administration & dosage ; Risk factors ; Risk groups ; Saliva ; Saliva - metabolism ; Stomach ; Stomach cancer ; Substance abuse treatment ; Thiols</subject><ispartof>PloS one, 2015-04, Vol.10 (4), p.e0120397</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication: https://creativecommons.org/publicdomain/zero/1.0/ (the “License”) Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c758t-1ec965a0b6b007e94bdb98831944dd1b2aae845d44e1da40eaa1e9c0786086433</citedby><cites>FETCH-LOGICAL-c758t-1ec965a0b6b007e94bdb98831944dd1b2aae845d44e1da40eaa1e9c0786086433</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382225/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382225/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2101,2927,23865,27923,27924,53790,53792,79471,79472</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25831092$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Mukaisho, Ken-ichi</contributor><creatorcontrib>Maejima, Ryuhei</creatorcontrib><creatorcontrib>Iijima, Katsunori</creatorcontrib><creatorcontrib>Kaihovaara, Pertti</creatorcontrib><creatorcontrib>Hatta, Waku</creatorcontrib><creatorcontrib>Koike, Tomoyuki</creatorcontrib><creatorcontrib>Imatani, Akira</creatorcontrib><creatorcontrib>Shimosegawa, Tooru</creatorcontrib><creatorcontrib>Salaspuro, Mikko</creatorcontrib><title>Effects of ALDH2 genotype, PPI treatment and L-cysteine on carcinogenic acetaldehyde in gastric juice and saliva after intragastric alcohol administration</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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.</description><subject>Acetaldehyde</subject><subject>Acetaldehyde - analysis</subject><subject>Acetaldehyde - metabolism</subject><subject>Acetaldehyde - toxicity</subject><subject>Adult</subject><subject>Alcohol dehydrogenase</subject><subject>Alcohol Drinking</subject><subject>Alcohol use</subject><subject>Alcoholic beverages</subject><subject>Aldehyde dehydrogenase</subject><subject>Aldehyde Dehydrogenase - genetics</subject><subject>Aldehyde Dehydrogenase, Mitochondrial</subject><subject>Beverage industry</subject><subject>Beverages</subject><subject>Cancer</subject><subject>Carcinogenesis</subject><subject>Carcinogens</subject><subject>Carcinogens - analysis</subject><subject>Carcinogens - metabolism</subject><subject>Carcinogens - toxicity</subject><subject>Cysteine</subject><subject>Cysteine - pharmacology</subject><subject>Cystine</subject><subject>Dairy products</subject><subject>Dehydrogenase</subject><subject>Enzymes</subject><subject>Esophageal cancer</subject><subject>Esophagus</subject><subject>Ethanol</subject><subject>Ethanol - 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Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Maejima, Ryuhei</au><au>Iijima, Katsunori</au><au>Kaihovaara, Pertti</au><au>Hatta, Waku</au><au>Koike, Tomoyuki</au><au>Imatani, Akira</au><au>Shimosegawa, Tooru</au><au>Salaspuro, Mikko</au><au>Mukaisho, Ken-ichi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effects of ALDH2 genotype, PPI treatment and L-cysteine on carcinogenic acetaldehyde in gastric juice and saliva after intragastric alcohol administration</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-04-01</date><risdate>2015</risdate><volume>10</volume><issue>4</issue><spage>e0120397</spage><pages>e0120397-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25831092</pmid><doi>10.1371/journal.pone.0120397</doi><tpages>e0120397</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2015-04, Vol.10 (4), p.e0120397 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1668244561 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS); EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Acetaldehyde Acetaldehyde - analysis Acetaldehyde - metabolism Acetaldehyde - toxicity Adult Alcohol dehydrogenase Alcohol Drinking Alcohol use Alcoholic beverages Aldehyde dehydrogenase Aldehyde Dehydrogenase - genetics Aldehyde Dehydrogenase, Mitochondrial Beverage industry Beverages Cancer Carcinogenesis Carcinogens Carcinogens - analysis Carcinogens - metabolism Carcinogens - toxicity Cysteine Cysteine - pharmacology Cystine Dairy products Dehydrogenase Enzymes Esophageal cancer Esophagus Ethanol Ethanol - analysis Ethanol - metabolism Fermentation Gastric cancer Gastric juice Gastric Juice - metabolism Gastric mucosa Gastric Mucosa - drug effects Gastric Mucosa - enzymology Gastric Mucosa - metabolism Genetic aspects Genotype Head Head & neck cancer Head and neck cancer Health risks Helicobacter pylori Humans Hydrogen-Ion Concentration Male Metabolism Oxidation Physiological aspects Proton pump inhibitors Proton Pump Inhibitors - administration & dosage Risk factors Risk groups Saliva Saliva - metabolism Stomach Stomach cancer Substance abuse treatment Thiols |
| title | Effects of ALDH2 genotype, PPI treatment and L-cysteine on carcinogenic acetaldehyde in gastric juice and saliva after intragastric alcohol administration |
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