• 11/2/2005
  • Bethesda, MD
  • Leslie Harris O’Hanlon
  • Journal of the National Cancer Institute, Vol. 97, No. 21, 1563-1564, November 2, 2005

Dozens of epidemiologic studies in the last several decades have shown an association between alcohol consumption and increased cancer risk. Now, laboratory studies are beginning to tease out the molecular mechanisms that may be at work.

Chronic alcohol consumption increases risk for cancers of the upper gastrointestinal tract. Alcohol is also associated with an increased risk of breast, colon, and liver cancer. Although many theories abound to explain the alcohol–cancer connection, alcohol metabolism is emerging as one of the main culprits.

Alcohol is broken down primarily in the liver by two enzymes. Alcohol dehydrogenase (ADH) converts ethanol into acetaldehyde, which collects in the blood, saliva, gastric juice, and large intestines. Acetaldehyde dehydrogenase (ALDH) then converts acetaldehyde into acetate, which is metabolized by tissues outside the liver.

In cell cultures and animal models, acetaldehyde is toxic, mutagenic, and carcinogenic. A recent study by researchers from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute of Standards and Technology (NIST) found that acetaldehyde can interact with polyamines—small molecules essential for cell division—to trigger a series of events that eventually lead to damaged DNA. When acetaldehyde was mixed with polyamines in a test tube, it was converted into crotonaldehyde (CrA), an environmental pollutant that has been shown to cause cancer in animals. This chemical in turn reacted with DNA, generating an abnormal, mutagenic DNA base called a Cr–PdG adduct. When unrepaired, adducts can cause mutations during DNA replication.

Previous studies have shown that acetaldehyde could be converted to Cr–PdG, but those studies used very high acetaldehyde concentrations—far higher than would ever occur in the human body. “We were able to demonstrate that these reactions can take place with acetaldehyde concentrations that have been measured in human saliva during alcohol consumption,” said P.J. Brooks, Ph.D., of the NIAAA and lead author of the report published in the August issue of Nucleic Acids Research. “This is a testable model in which alcohol is converted to acetaldehyde, which gets into cells and reacts with polyamines to form the Cr–PdG adduct. That adduct can plausibly give rise to chromosomal aberrations, which has previously been observed in cells treated with acetaldehyde.”

Genetic linkage studies have shown that people who have polymorphisms in the genes that code for the two enzymes responsible for alcohol metabolism have much higher rates of upper gastrointestinal tract cancers. Between 30% and 50% of all Asians have some ALDH activity but are unable to metabolize acetaldehyde as thoroughly as individuals who have a normally functioning enzyme. Also, about 5% of white people have a genetic polymorphism of the enzyme ADH that causes them to metabolize alcohol much more rapidly than individuals with normal ADH. As a result, all these individuals have elevated salivary acetaldehyde levels, which puts them at greater risk of upper gastrointestinal cancers, explained Mikko Salaspuro, M.D., Ph.D., a professor at the Research Unit of Substance Abuse Medicine at University Central Hospital in Helsinki, Finland.

Smoking and drinking can increase salivary acetaldehyde levels as well. Tobacco not only contains acetaldehyde but when smoked also changes the oral bacterial flora, which can cause a production of more acetaldehyde from alcohol in the saliva. Smoking can also increase acetaldehyde levels in the colon and large intestine.

“Drinking and smoking can be a dangerous combination,” said Helmut Seitz, M.D., director of the Salem Medical Center and Laboratory of Alcohol Research, Liver Disease, and Nutrition in Heidelberg, Germany, and vice president of the European Society for Biomedical Research on Alcoholism. “For example, if a patient drinks one bottle of wine every day for 10–20 years, he has an 18-fold risk of developing esophageal cancer. If he doesn’t drink, but smokes 20 cigarettes a day for 10–20 years, he has a fivefold risk. If he smokes and drinks, he has a 45-fold risk.”

The enzyme cytochrome P450 2E1 (CYP2E1) is another critical player in alcohol-induced cancer. CYP2E1 is involved in the metabolism of foreign chemicals in the body, such as alcohol. The more a person drinks, the higher the level of CYP2E1, Seitz said. This enzyme produces reactive oxygen species—free radicals generated during oxidative metabolism—which can lead to the formation of DNA adducts and interfere with DNA repair mechanisms.

A recent study in mice found that heavy alcohol use can lead to oxidative damage. When the mice were treated with an amount of ethanol equivalent to a human consuming a bottle of whiskey every day for 4 weeks, oxidative stress damaged their DNA. Mice that were genetically engineered to be missing CYP2E1 were protected from this effect, although they showed signs of liver damage. Mice with normal CYP2E1 levels had oxidative damage, another possible implication of CYP2E1’s role in the alcohol–cancer connection.

“If people consume alcohol chronically, this load of oxidative DNA damage will persist and might create conditions favorable to certain cells in tissue to acquire enough DNA damage and mutations that may either inactivate proteins controlling cell proliferation or activate proteins that push cells to proliferate uncontrollably,” said the study’s author, Ivan Rusyn, M.D., Ph.D., an investigator at the University of North Carolina’s Bowles Center for Alcohol Studies and assistant professor at the Department of Environmental Sciences and Engineering at the School of Public Health in Chapel Hill.

Although the evidence is strongest for the association between the incidence of upper gastrointestinal tract cancer and chronic and heavy alcohol consumption, evidence is also emerging about the role of alcohol in breast cancer. Alcohol consumption is associated with a small but consistent increase in breast cancer risk. However, what is different about breast cancer is that, unlike other cancers, breast cancer may be spurred by relatively low doses of alcohol.

A study published in the October 2004 issue of the International Journal of Oncology found that women who drank moderately and who carried a mutant version of the ADH gene that caused rapid acetaldehyde breakdown were 1.8 times more likely to develop breast cancer than women who did not have the mutant gene. The same study also found estrogen levels were 27%–38% higher in women who consumed a small quantity of alcohol—an amount just slightly over one drink—during various parts of their menstrual cycle than in women who had not consumed alcohol.

And, in this issue of the Journal of the National Cancer Institute, researchers from the Karolinska Institute in Stockholm report an association between alcohol intake and an increased risk of developing estrogen receptor–positive breast cancer in postmenopausal women. (See p. 1601.)

“The risk has been reported multiple times. We don’t know the exact reasons why, though there are lots of theories,” said Peter Shields, M.D., professor of medicine and oncology and director of Cancer Genetics and Epidemiology at Georgetown University Medical Center in Washington, D.C.

Those theories include the possibility that alcohol affects estrogen levels, free radical levels, acetaldehyde levels, and folic acid status. Also, Georgetown researchers are studying how alcohol can affect genes that control estrogen levels, folic acid status, and DNA repair and methylation, a process that may activate oncogenes or inactivate tumor suppressor genes.

Other researchers are looking at an entirely different avenue by which alcohol may aid cancer formation and progression. Through a series of animal experiments in chick embryos, Jian-Wei Gu, M.D, a researcher at the University of Mississippi Medical Center in Jackson, found that alcohol stimulates tumor growth, angiogenesis, metastasis, and vascular endothelial growth factor expression in tumors.

The immune system usually eliminates new tumors if there are no blood vessels to aid growth, Gu explained. But drinking alcohol might put the wheels of angiogenesis in motion, causing tumors to grow bigger, making them much more difficult for the immune system to destroy. Gu is currently testing his hypothesis in a mouse model. Preliminary data indicate the mice are showing the same effects as the chick embryos when given the equivalent of two to three alcoholic drinks per day in humans.

The U.S. Department of Health and Human Services listed alcohol as a known human carcinogen in 2000. One of the toughest questions is at what level of alcohol consumption carcinogenic effects take place. The general consensus is the more alcohol a person consumes, the higher the cancer risk. Many health organizations state that men should drink no more than two drinks a day and women no more than one drink per day.