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Defective Enzyme Fights Smoking.

BETHESDA, MD. -- People with a defective liver enzyme are twice as likely to avoid becoming addicted smokers than are those with a functional enzyme, Rachel F. Tyndale, Ph.D., said at a meeting on nicotine addiction sponsored by the National Institute on Drug Abuse.

The protective effect extends to addicted smokers: Those with the enzyme defect require fewer cigarettes to maintain nicotine levels in the blood and brain, said Dr. Tyndale of the department of pharmacology at the University of Toronto.

Improved understanding of the enzyme's effects might lead to new approaches to preventing and treating nicotine addiction, she said.

Dr. Tyndale and her colleagues identified the cytochrome P-450 isoenzyme 2A6 (CYP2A6) as the major pathway for nicotine removal. About 60%-80% of nicotine is metabolized and inactivated to cotinine, primarily by CYP2A6. A mutation in one or both of the alleles for CYP2A6 drastically slows nicotine metabolism, they found.

"Carriers of CYP2A6 defective alleles are protected from tobacco dependance, smoke fewer cigarettes, and have a decreased activation of tobacco-specific pro-carcinogens to carcinogens," Dr. Tyndale said at the meeting, also sponsored by the Robert Wood Johnson Foundation.

A person may have two normal genes for CYP2A6, and therefore normal nicotine metabolism; one active and one defective copy, with reduced metabolism; or two defective copies, with a further reduction in nicotine metabolism.

"Impaired nicotine metabolism protects a smoker against becoming dependent," she and her colleagues reported earlier (Nature 393[6687]:750, 1998).

Updated findings from the study showed that the prevalence of a defective CYP2A6 enzyme in a group of 213 nonsmokers who had tried cigarettes was 20%, compared with only 10% in a group of 317 nicotine-dependent smokers.

"While its impact is limited in that it is only one of the genes that is important, it is having a profound impact in helping to determine who becomes a smoker and who doesn't," Dr. Tyndale said, noting that a defective CYP2A6 enzyme "protects about 7 million North Americans from becoming smokers."

The adverse effects of learning to smoke, such as dizziness or nausea, may last longer in an individual with impaired nicotine metabolism, As a result, these individuals could be less likely to become dependent smokers, she said.

The researchers also found that dependent smokers with one mutated CYP2A6 allele smoked an average of 30 fewer cigarettes per week than did smokers with two normal alleles. That effect was greater in males, probably because females seem to regulate their smoking less specifically for nicotine than do males, she said.

Dr. Tyndale and her associates could not calculate the smoking rate for individuals with a mutation in both CYP2A6 alleles, a pattern that occurs in only about 1.5% of the nonsmoking population.

Dependent smokers adjust the number of cigarettes they smoke to maintain a constant blood and brain nicotine concentration. Because an impaired CYP2A6 enzyme provides the individual with higher levels of nicotine for a longer time, dependent smokers with the defect need to smoke fewer cigarettes in order to maintain their nicotine level, Dr. Tyndale explained.

The discovery of CYP2A6's role may open the door to new approaches to smoking prevention and cessation. It may be possible to imitate the genetic defect by blocking the enzyme in dependent smokers who have a functional CYP2A6 allele, she said.
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Publication:Family Practice News
Article Type:Brief Article
Geographic Code:1U5MD
Date:Sep 1, 1998
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