title: Demonstration of ethanol-induced protein adducts in oral leukoplakia (pre-cancer) and cancer.
abstract: BACKGROUND
  Excessive alcohol consumption is a common cause for upper gastrointestinal tract cancers. However, the primary mechanisms of alcohol-induced carcinogenesis have remained poorly defined.
  
  
  METHODS
  We examined the generation and subcellular distribution of protein adducts with acetaldehyde (AA), the first metabolite of ethanol, and end products of lipid peroxidation, malondialdehyde (MDA) and 4-hydroxynonenal (HNE), from oral biopsy specimens obtained from 36 subjects (11 British, 25 Japanese) reporting alcohol misuse. All patients had been diagnosed with oral pre-cancer (leukoplakia, n = 7) or squamous cell carcinoma (SCC; n = 29). Automated immunostaining for AA, MDA and HNE adducts was performed using monospecific antibodies.
  
  
  RESULTS
  Positive staining for AA, MDA and HNE adducts was observed in the dysplastic or malignant epithelial cells, HNE being relatively the most abundant adduct species. The subgroup of Japanese patients had higher levels of AA and MDA, although not HNE, than the British sample. When the material was divided to those with SCC or leukoplakia, MDA adducts but not the other antigens were more prominent in the former group. Significant correlations were found between the different adducts (AA vs. MDA, r = 0.68, P < 0.001; AA vs. HNE, r = 0.47, P < 0.01 and MDA vs. HNE, r = 0.59, P < 0.001). In addition, cytochrome P450 2E1 staining was found in these samples, correlating with both AA and MDA adducts.
  
  
  CONCLUSIONS
  The data indicates that AA- and lipid peroxidation-derived adducts are formed in oral tissues of alcohol misusers with oral leukoplakia and cancer. The findings also support a pathogenic role of AA and excessive oxidative stress in carcinogenesis.
authors.affiliation: Department of Oral Medicine, King's College London Dental Institute at Guy's, King's & St Thomas' Hospitals, WHO Collaborating Centre for Oral Cancer and Precancer, London, UK.
authors.forename: Saman
authors.initials: S
authors.lastname: Warnakulasuriya
authors.forename: Seppo
authors.initials: S
authors.lastname: Parkkila
authors.forename: Toru
authors.initials: T
authors.lastname: Nagao
authors.forename: Victor R
authors.initials: VR
authors.lastname: Preedy
authors.forename: Markku
authors.initials: M
authors.lastname: Pasanen
authors.forename: Heidi
authors.initials: H
authors.lastname: Koivisto
authors.forename: Onni
authors.initials: O
authors.lastname: Niemelä
mesh_terms: D000079:Acetaldehyde / Q000378:metabolism; D000437:Alcoholism / Q000150:complications / Q000378:metabolism*; D000447:Aldehydes / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000378:metabolism*; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis; D000431:Ethanol / Q000009:adverse effects / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007564:Japan; D007972:Leukoplakia, Oral / Q000209:etiology / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000502:physiology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000209:etiology / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D011485:Protein Binding; D006113:United Kingdom
chemical_list: D000447:Aldehydes; D000431:Ethanol; D008315:Malondialdehyde; D019392:Cytochrome P-450 CYP2E1; D000079:Acetaldehyde; C027576:4-hydroxy-2-nonenal