Fine-Tuning the Search for Biochemical Characteristics of Alcoholics

• Genetic factors are known to contribute to the development of alcoholism
• Biochemical characteristics can help identify those people with a predisposition for alcoholism
• The enzyme platelet adenylyl cyclase may be such a biochemical marker
• The marker seems to work best among abstinent drinkers

Numerous family, twin and adoption studies have provided evidence that genetic factors contribute to the development of alcoholism. A related focus of alcohol research is the search for biochemical characteristics, also know as markers, that could distinguish people who are alcoholic from people who are not, or between people who have a predisposition for alcoholism and those who do not. A study published in the June issue of Alcoholism: Clinical & Experimental Research may have found a biochemical marker for alcohol dependence: activity levels of the enzyme platelet adenylyl cyclase (AC).

"Our findings go beyond the assertions that alcoholism or other addictive disorders may have genetic components," said Boris Tabakoff, chair of the Department of Pharmacology, University of Colorado School of Medicine and lead author of the study. "We are specifying at least one possible set of genetically determined differences that may identify individuals predisposed to alcoholism or other addictions."

Adenylyl cyclase (AC) is an enzyme used by cells, including the brain’s neurons, to relay signals from a cell’s exterior to its interior. A cell can receive both inhibitory and stimulatory exterior signals. During the past decade or so, researchers have found that AC activity in the platelets of alcoholic subjects is lower than in the blood cells of nonalcoholics.

This study expands upon previous research on several different levels. First, it found that among abstinent drinkers, platelet AC activities were significantly lower in those individuals with either current or lifetime alcohol dependency than in those individuals with no history of alcohol dependence. This means that if these findings can be replicated, and the techniques used to measure platelet AC activity can be streamlined and made more economical, such a test could potentially be used to screen high-risk populations (such as children of alcoholics). In theory, such a test would allow early identification of those vulnerable for developing alcoholism, individuals who would benefit from targeted prevention and intervention strategies. Second, the study found that recent alcohol consumption (within two to four days) was a confounding variable that can alter the measured levels of AC activity.

"Some other studies have not always carefully measured the length of time that someone is abstinent from alcohol," explained Robert M. Anthenelli, associate professor of psychiatry in the College of Medicine at the University of Cincinnati, and director of substance dependence programs at the Cincinnati Veterans Affairs Medical Center. "Yet this might influence the way these biological markers can be detected. Another strength of this study is the way it considered numerous other alcoholism-related variables such as cigarette smoking. The vast majority of alcoholics smoke cigarettes. Some previous assessments of biological makers have attributed some things to alcoholism which were, in fact, related to cigarette smoking."

This particular study did not find that cigarette smoking, age or body weight had a discernible effect on platelet AC activity. However, it did find that in addition to alcohol dependence, a history of major depression, hyperlipidemia (high levels of circulating fats in the blood) and a family history of alcohol dependence appeared to contribute to low platelet AC activity. Although depression and hyperlipidemia may be independent of alcoholism, in the current study these factors may have been associated with intake of large quantities of alcohol.

Both Tabakoff and Anthenelli noted another strength of the study: its subjects. "Prior studies of AC mainly compared clinical samples, meaning individuals in treatment," explained Tabakoff, "with nonalcoholic individuals. Here we looked at more than two hundred people, some of them were in treatment, and some were recruited by advertisement. Out of this population sample, we once again found the same differences in platelet AC activity that we found with pre-selected dependent and nondependent individuals. Even larger population studies would help substantiate this as a good marker."

Anthenelli is excited about the research possibilities that exist. "If we could identify a reliable, valid biological marker of alcoholism," he said, "then at least in theory we could also begin to track back, to see what genes are controlling that enzyme. Down the road, we could potentially develop a screening genetic test to see which people are at risk for developing alcoholism because they have an abnormality in that gene or other genes."

That is, in fact, what Tabakoff proposes to do. "We have identified the gene that determines cyclase activity in platelets," he said, "and have located its chromosomal location. Now we’re going to be looking for polymorphisms or differences in that gene in alcoholics, children of alcoholics, and nonalcoholics."