Interaction of alcohol, colonic bacteria and genes in the pathogenesis of colorectal cancer

Chronic alcohol consumption is a risk factor for colorectal cancer. Although this risk is smaller as compared to the upper alimentary tract, the relative risk of 2–3, especially for the rectum, is of importance, considering the high prevalence of this tumour in the Western World. In animal experiments it has been shown that chronic alcohol consumption enhances chemically induced colorectal carcinogenesis. Such a stimulation of experimental colorectal carcinogenesis is not only observed with secondary procarcinogens which need metabolic activation to become ultimative carcinogens, but also when a direct locally acting carcinogen, such as acetoxymethyl-methyl-nitrosamine is applied to the mucosa. Using this carcinogen, it has been shown that colorectal carcinogenesis is accelerated in chronically alcohol exposed animals and that this carcinogenic effect is due to acetaldehyde. When acetaldehyde dehydrogensase is inhibited by cyanamide which leads to increased acetaldehyde concentrations in the blood but also in the colon, an early occurrence of tumours is observed. This effect was found to be attenuated in germ-free animals, suggesting that bacteria may be involved in this process. Alcohol can be metabolized to acetaldehyde in the colorectal mucosa by ADH1B, ADH1C and ADH5. This metabolism is relatively small compared to the generation of acetaldehyde by faecal bacterial enzymes. Bacterial conversion from ethanol to acetaldehyde leads to high acetaldehyde concentrations which are approximately 4–5 times higher than those observed in the liver per gram of tissue. The levels of acetaldehyde in the colonic mucosa correlate with crypt cell production rate. The more acetaldehyde is present, the higher is cell turnover. Colonic mucosal hyperregeneration is, however, an early event in carcinogenesis. Furthermore, acetaldehyde in concentrations present in the colon may destroy folate, which is an important factor in carcinogenesis. It has been shown that low folate and methionine levels together with a moderate alcohol intake resulted in a 7-fold increased risk for distal colorectal cancer. Folate deficiency participates in the disturbed methyl transfer in the alcoholic, leading to DNA hypomethylation. Finally, genetic linkage studies in humans have demonstrated that acetaldehyde plays a causal role in colorectal carcinogenesis. This has been shown in Japanese who carry a mutation of the acetaldehyde dehydrogenase 2 (ALDH2) which results in a low activity of ALDH2. These individuals have a 3-fold increased risk for colorectal cancer when they drink alcohol. More recently, preliminary data in Caucasians have shown that individuals with an alcohol dehydrogenase (ADH) 1C*1/1 homozygosity also have an increased risk for colorectal cancer. The ADH1C*1 allele encodes for an enzyme with a 2.5-fold increase of acetaldehyde production as compared to the ADH1C*2 allele. Subsequently, chronic alcohol consumption also induces cytochrome P4502E1 (CYP2E1) in colorectal mucosa. This induction is associated with the production of reactive oxygen species (ROS) which may damage DNA. Intervention with a-tocopherol, a scavenger of ROS, attenuates the colorectal hyperproliferation observed after chronic alcohol consumption. It has recently been shown that the induction of CYP2E1 differs individually. In summary and conclusion, there is overwhelming evidence that acetaldehyde is not only involved in upper alimentary tract cancer, but also in colorectal cancer in heavy drinkers. In the large intestine, genetic-environmental interaction between faecal bacteria and genes involved in alcohol metabolism may modify cancer risk in the alcoholic.