Effect of ethanol on nitrosamine metabolism and distribution. Implications for the role of nitrosamines in human cancer and for the influence of alcohol consumption on cancer incidence.

For reasons that have never been explained, the consumption of alcohol is associated with an increase in the incidence of human cancer, notably that of the oesophagus. The effect of ethanol on nitrosamine metabolism and carcinogenicity is reviewed, together with new work on pharmacokinetics. This work shows that small quantities of ethanol alter the distribution and metabolism of small oral doses of N-nitrosodimethylamine and N-nitrosodiethylamine in rats, to increase by several fold the alkylation of DNA in organs that are particularly susceptible to their carcinogenic effect. It is shown that in the case of N-nitrosodimethylamine this is the result of prevention of first-pass clearance of the nitrosamine as it travels in the blood draining the gut through the liver before entering the general circulation. There is evidence that the same happens in man. These results explain the findings from various experiments in animals and they lend credence to the observation that nitrosamines occur in human blood after high-nitrate meals are taken with alcohol. The results have led to the hypothesis that the influence of alcohol consumption on human cancer may be mediated through the effect of ethanol on the pharmacokinetics of nitrosamines derived from diet, from tobacco smoke and from endogenous synthesis. The evidence for this hypothesis and its wider implications are discussed.