Background: Chronic ethanol consumption is associated with an increased risk of upper aerodigestive tract cancer. As acetaldehyde seems to be a carcinogenic factor associated with chronic alcohol consumption, alcoholics with the alcohol dehydrogenase (ADH) 1C*1 allele seem to be particularly at risk as this allele encodes for a rapidly ethanol metabolising enzyme leading to increased acetaldehyde levels. Recent epidemiological studies resulted in contradictory results and therefore we have investigated ADH1C genotypes in heavy alcohol consumers only. Methods: We analysed the ADH1C genotype in 107 heavy drinkers with upper aerodigestive tract cancer and in 103 age matched alcoholic controls without cancer who consumed similar amounts of alcohol. Genotyping of the ADH1C locus was performed using polymerase chain reaction based on restriction fragment length polymorphism methods on leucocyte DNA. In addition, ethanol was administered orally (0.3 g/kg body weight) to 21 healthy volunteers with the ADH1C*1,1, ADH1C*1,2, and ADH1C*2,2 genotypes, and 12 volunteers with various ADH genotypes consumed ethanol ad libitum (mean 211 (29) g). Subsequently, salivary acetaldehyde concentrations were measured by gas chromatography or high performance liquid chromatography. Results: The allele frequency of the ADH1C*1 allele was found to be significantly increased in heavy drinkers with upper aerodigestive tract cancer compared with age matched alcoholic controls without cancer (61.7% v 49.0%; p = 0.011). The unadjusted and adjusted odds ratios for all cancer cases versus all alcoholic controls were 1.67 and 1.69, respectively. Healthy volunteers homozygous for the ADH1C*1 allele had higher salivary acetaldehyde concentrations following alcohol ingestion than volunteers heterozygous for ADH1C (p = 0.056) or homozygous for ADH1C*2 (p = 0.011).Conclusions: These data demonstrate that heavy drinkers homozygous for the ADH1C*1 allele have a predisposition to develop upper aerodigestive tract cancer, possibly due to elevated salivary acetaldehyde levels following alcohol consumption.
Heavy drinking is associated with many gastrointestinal symptoms and diseases, such as rapid intestinal transit time, diarrhea, colon polyps, and colorectal cancer. Acetaldehyde produced from ethanol by intestinal microbes has recently been suggested to be one of the pathogenetic factors related to alcohol-associated gastrointestinal morbidity. Furthermore, acetaldehyde is absorbed from the colon into portal blood and may thus contribute to the development of alcoholic liver injury. The present study was aimed to investigate the significance of gut aerobic flora in intracolonic acetaldehyde formation. For this study, 58 male Wistar rats (aged 9 to 11 weeks) were used. Half of the rats received ciprofloxacin for four consecutive days. Control rats (n = 29) received standard chow. On the fifth day of treatment, 1.5 g/kg body weight of ethanol was administered intraperitoneally to 19 rats receiving ciprofloxacin and 19 control rats. Ten ciprofloxacin-treated and 10 control rats received equal volumes of physiological saline intraperitoneally. Two hours after the injection of ethanol or saline, the samples of colonic contents and blood were obtained. Acetaldehyde and ethanol levels of the samples were determined by headspace gas chromatography. The intracolonic acetaldehyde level 2 hr after ethanol administration was 483+/-169 microM (maximum: 2.7 mM). High intracolonic acetaldehyde after ethanol injection was significantly reduced by ciprofloxacin treatment. After ciprofloxacin, intracolonic acetaldehyde levels before and after the injection of ethanol were 25+/-4.8 and 23+/-15 microM, respectively. Ciprofloxacin treatment resulted also in significantly higher blood (p < 0.005) and intracolonic (p < 0.0001) ethanol levels than in the control animals. Furthermore, ciprofloxacin treatment totally abolished the formation of endogenous ethanol in the large intestine. This study demonstrates that alcoholic fermentation and intracoIonic acetaldehyde production can be blocked by diminishing the amount of intracolonic aerobic bacteria with ciprofloxacin. Our findings indicate that the bacteriocolonic pathway for ethanol oxidation is mediated almost exclusively by gut aerobic microbes, and this knowledge may provide new insights into the studies on the pathogenesis of alcohol-related gastrointestinal symptoms and diseases.
This study demonstrates that during ethanol challenge, intracolonic acetaldehyde level is regulated not only by intracolonic microbes, but also by colonic mucosal cells.
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