Demonstration of ethanol-induced protein adducts in oral leukoplakia (pre-cancer) and cancer.
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.
Warnakulasuriya
Saman
S
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.
Parkkila
Seppo
S
Nagao
Toru
T
Preedy
Victor R
VR
Pasanen
Markku
M
Koivisto
Heidi
H
Niemelä
Onni
O
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
D000447:Aldehydes; D000431:Ethanol; D008315:Malondialdehyde; D019392:Cytochrome P-450 CYP2E1; D000079:Acetaldehyde; C027576:4-hydroxy-2-nonenal