CYP2A6 Variation May Protect Against Nicotine Addiction

A gene variant in the CYP2A6 enzyme may help protect some individuals from nicotine addiction, according to a new study funded in part by the National Institute on Drug Abuse of the National Institutes of Health.

According to the study, which was published in a recent issue of Nature, individuals with decreased functionality of CYP2A6 were shown to have greater resistance to nicotine addiction and, if they do smoke, smoke fewer cigarettes than do individuals without the variant gene.

CYP2A6, found in the liver, is primarily responsible for metabolizing nicotine. University of Toronto researchers, led by Rachel F. Tyndale, Ph.D., observed that CYP2A6 variation affects the metabolism of nicotine. Individuals with decreased functional CYP2A6 are less likely to become addicted to nicotine.

Tyndale and her colleagues found three different gene types, or alleles, for CYP2A6: a normal, or wild-type allele, that is fully functional; and two null or inactive alleles. Individuals with the null alleles functionally lack the enzyme and are unable to break down nicotine to cotinine, a major metabolite of nicotine.

When comparing a group of smokers to a group that had tried tobacco but had never become addicted to it, the investigators found that individuals in the nonaddicted group were much more likely to have impaired nicotine metabolism, and to have one null allele for CYP2A6. Thus, those with a null allele had been "protected" against nicotine addiction compared with individuals with the normal or wild-type alleles.

In addition, among a group of people who do smoke regularly, those with null CYP2A6 alleles smoked fewer cigarettes over the course of a week than those with normal CYP2A6 alleles.

Tyndale said, "These two factors, a reduced propensity to smoke and the need to smoke less, would likely decrease the risk of developing tobacco-related illnesses, such as cancer, among those with CYP2A6-null alleles."

Researchers believe that the protective effect of CYP2A6-null alleles suggests that medications might be developed that can inhibit the enzyme, thus providing innovative approaches to preventing and treating nicotine addiction-LKC