Alcohol and cancer

March 14, 2002

Cancer, the often-deadly process during which normal body cells are transformed into malignant ones, likely involves change in the genetic material of the cells known as deoxyribonucleic acid (DNA). Oncogenes are those genes that regulate cell growth, proliferation, and repair of tissues. Oncogenes are also the targets of carcinogenic agents such as asbestos, ultraviolet rays of the sun, and cigarette smoking. A study in the March issue of Alcoholism: Clinical & Experimental Research investigates if alcohol exposure can increase the cytotoxicity (cell destructiveness) of known carcinogenic agents that could, in turn, damage DNA and lead to mutation or cancer.

"We are bombarded by potential carcinogenic agents everyday in our environment," said Richard A. Deitrich, professor of pharmacology at the University of Colorado Health Science Center. "Most of these do not cause cancer, but given a boost from alcohol, some of them may."

"Epidemiological studies have shown that drinking alcohol is associated with an increased risk of tumors in the esophagus, mouth, larynx and liver," noted David B. Couch, associate professor of pharmacology and toxicology at the University of Mississippi and lead author of the study. "Blood cells of alcoholics also have a greater incidence of genetic damage than do members of the general population. It has been unclear, however, if alcohol itself causes these effects. The key finding of our study was to show that, in the model system used, alcohol exposure could produce effects consistent with inhibition of the base excision repair pathway." In other words, alcohol appears to contribute to genetic damage by impairing DNA repair processes.

Researchers tested the survival capabilities of Chinese hamster ovary A10 cells by exposing them to alcohol, genotoxicants (substances that can damage DNA through mutation or cancer), and non-DNA reactive cytotoxic agents. A10 cells were chosen because they have been engineered to express alcohol dehydrogenase (ADH), which is known to convert alcohol to acetaldehyde (AcHO). AcHO belongs to a class of compounds called aldehydes (such as formaldehyde, a disinfectant and preservative), and is well known as a highly reactive and toxic compound that can damage the cells of all living things. Normally when people drink, alcohol is converted to AcHO in the liver, which is then rapidly metabolized to acetate, which is then further metabolized by tissues outside of the liver.

The specific genotoxicants used in the experiment were 1-methyl-3-nitro-1-nitrosoguanidine, ethyl methanesulfonate, 4-nitroquinoline-N-oxide, ICR 170, and mitomycin C. Also used was 6-thioguanine, which damages DNA but not directly. The non-DNA reactive compounds used were ouabain, cycloheximide, and colchicine. In addition, an inhibitor of ADH called 4-methylpyrazole was given to some of the A10 cells in order to establish if alcohol or its metabolite acetaldehyde was responsible for cell damage.

"The major finding of this study is that alcohol causes an increase in the mutagenicity (the capacity to induce mutations) of agents that damage DNA," said Deitrich. "This is as a result of the metabolism of alcohol to acetaldehyde. In fact, it is clear that acetaldehyde is the major culprit in the effects noted here. The presumption is that it is acetaldehyde itself that is causing the damage, but it could be other aldehydes as well. For example, acetaldehyde may interfere with the normal cellular mechanisms designed to inactivate endogenous aldehydes, those produced in normal cellular function or those produced as a result of alcohol's production of oxidative damage."

"Acetaldehyde is highly reactive," added Couch. "It can react with amino groups on proteins, which could potentially interfere with the function of the protein. Of course, acetaldehyde can also react with other cellular constituents, including DNA."

Couch and Deitrich both noted that, even though researchers have known for a long time that alcohol increases the risk of cancer, relatively little attention has been paid to the genotoxic implications of exposure to alcohol. Deitrich had several suggestions for future research directions, some of which Couch and his colleagues already plan to pursue.

"It would seem reasonable to dissect the mechanism(s) by which DNA damage takes place," said Deitrich. "For example, what specific DNA damage is done, and why can't the cells repair this damage? What implications does this research have for about half of the Asian population who lack the ability to efficiently metabolize acetaldehyde? Does this relate to their greater risk of liver damage if they do drink? What implications does this have for alcoholics who are treated with Antabus (containing disulfiram) which increases the level of acetaldehyde in the body if they drink? What implications does this have for these people even if they do not drink, since Antabus inhibits the metabolism of endogenous aldehydes as well? Finally," he added, "perhaps the most important future research would be to demonstrate that acetaldehyde levels that are found in the 'normal' range after alcohol consumption will also cause this damage."
The co-author of the Alcoholism: Clinical & Experimental Research paper was Rodney C. Baker of the Department of Pharmacology and Toxicology at the University of Mississippi Medical Center. The study was funded by the Centers for Disease Control and Prevention.

Alcoholism: Clinical & Experimental Research

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