PMID- 25831092
OWN - NLM
STAT- MEDLINE
DCOM- 20160405
LR  - 20240326
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 10
IP  - 4
DP  - 2015
TI  - Effects of ALDH2 genotype, PPI treatment and L-cysteine on carcinogenic 
      acetaldehyde in gastric juice and saliva after intragastric alcohol 
      administration.
PG  - e0120397
LID - 10.1371/journal.pone.0120397 [doi]
LID - e0120397
AB  - 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.
FAU - Maejima, Ryuhei
AU  - Maejima R
AD  - Division of Gastroenterology, Tohoku University Graduate School of Medicine, 
      Sendai, Japan.
FAU - Iijima, Katsunori
AU  - Iijima K
AD  - Division of Gastroenterology, Tohoku University Graduate School of Medicine, 
      Sendai, Japan.
FAU - Kaihovaara, Pertti
AU  - Kaihovaara P
AD  - Research Unit on Acetaldehyde and Cancer, University of Helsinki, Helsinki, 
      Finland.
FAU - Hatta, Waku
AU  - Hatta W
AD  - Division of Gastroenterology, Tohoku University Graduate School of Medicine, 
      Sendai, Japan.
FAU - Koike, Tomoyuki
AU  - Koike T
AD  - Division of Gastroenterology, Tohoku University Graduate School of Medicine, 
      Sendai, Japan.
FAU - Imatani, Akira
AU  - Imatani A
AD  - Division of Gastroenterology, Tohoku University Graduate School of Medicine, 
      Sendai, Japan.
FAU - Shimosegawa, Tooru
AU  - Shimosegawa T
AD  - Division of Gastroenterology, Tohoku University Graduate School of Medicine, 
      Sendai, Japan.
FAU - Salaspuro, Mikko
AU  - Salaspuro M
AD  - Research Unit on Acetaldehyde and Cancer, University of Helsinki, Helsinki, 
      Finland.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150401
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Carcinogens)
RN  - 0 (Proton Pump Inhibitors)
RN  - 3K9958V90M (Ethanol)
RN  - EC 1.2.1.3 (ALDH2 protein, human)
RN  - EC 1.2.1.3 (Aldehyde Dehydrogenase)
RN  - EC 1.2.1.3 (Aldehyde Dehydrogenase, Mitochondrial)
RN  - GO1N1ZPR3B (Acetaldehyde)
RN  - K848JZ4886 (Cysteine)
SB  - IM
MH  - Acetaldehyde/analysis/*metabolism/toxicity
MH  - Adult
MH  - Alcohol Drinking
MH  - Aldehyde Dehydrogenase/*genetics
MH  - Aldehyde Dehydrogenase, Mitochondrial
MH  - Carcinogens/analysis/*metabolism/toxicity
MH  - Cysteine/*pharmacology
MH  - Ethanol/analysis/metabolism
MH  - Gastric Juice/*metabolism
MH  - Gastric Mucosa/drug effects/enzymology/metabolism
MH  - Genotype
MH  - Humans
MH  - Hydrogen-Ion Concentration
MH  - Male
MH  - Proton Pump Inhibitors/*administration & dosage
MH  - Saliva/*metabolism
PMC - PMC4382225
COIS- Competing Interests: In this study, KI received funding from commercial sources 
      (Astra Zeneca PLC, Biohit Oyj., Eisai Co., Ltd., Takeda Pharmaceutical Co., Ltd). 
      MS is a board member and medical adviser of Biohit Oyj. However, the authors 
      confirm that this does not alter their adherence to PLOS ONE policies on sharing 
      data and materials.
EDAT- 2015/04/02 06:00
MHDA- 2016/04/06 06:00
PMCR- 2015/04/01
CRDT- 2015/04/02 06:00
PHST- 2014/11/19 00:00 [received]
PHST- 2015/01/21 00:00 [accepted]
PHST- 2015/04/02 06:00 [entrez]
PHST- 2015/04/02 06:00 [pubmed]
PHST- 2016/04/06 06:00 [medline]
PHST- 2015/04/01 00:00 [pmc-release]
AID - PONE-D-14-52004 [pii]
AID - 10.1371/journal.pone.0120397 [doi]
PST - epublish
SO  - PLoS One. 2015 Apr 1;10(4):e0120397. doi: 10.1371/journal.pone.0120397. 
      eCollection 2015.