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Genes may influence how much you smoke
By Bijal P. Trivedi

A personís tendency to have the occasional cigarette or to become a chronic chain smoker seems to lie in the genes.

The cytochrome P450 2A6 (CYP2A6) gene, which makes an enzyme of the same name, controls the speed with which nicotine is removed from the body. Blocking the activity of the CYP2A6 enzyme may help smokers decrease the amount of smoke inhaled by about 30 percent, according to results presented at the March meeting of the American Society for Clinical Pharmacology and Therapeutics in Los Angeles.

As long as nicotine stays in the blood, the smoker experiences the stimulating effects of the drug. But as the CYP2A6 enzyme converts nicotine into cotinine, which is then excreted, the nicotine levels fall and the smoker craves another cigarette.

In a small three-day clinical trial researchers gave 11 smokers small doses of Methoxsalen, a drug known to disrupt nicotine processing in the body, and asked the subjects to keep smoking the same number of cigarettes each day, says Edward Sellers, of the University of Toronto. Sellers and co-author Rachel Tyndale found that while the smokers consumed about the same number of cigarettes, "they couldnít smoke the same way with the same intensity, and inhaled about 30 percent less smoke," says Sellers.

Methoxsalen—previously used as a drug to treat psoriasis—prevents the CYP2A6 enzyme from converting nicotine into cotinine. It also prevents CYP2A6 from activating cancer-causing compounds in cigarette smoke. Without the CYP2A6 enzyme, nicotine remains in the blood producing a longer high, and the body eventually shunts the nicotine into a series of detoxification steps without activating cancerous agents.

"The potential value of methoxsalen is that it can help smokers change their smoking habits, reducing the number of cigarettes a person smokes from 40 to 15 cigarettes per day for example," says Tyndale.

But not everyone has exactly the same version a CYP2A6 gene. In fact, some do not have the gene at all.

In a second study of 200 light and 200 heavy smokers, Tyndale and Sellers found that those with slight variations in their CYP2A6 gene smoked about six fewer cigarettes per day and had lower carbon monoxide levels in their breath—a measure of smoking exposure. These different versions of the gene confer protection upon the smoker by processing nicotine less efficiently.

"Having certain mutant versions of the CYP2A6 gene or not having the CYP2A6 gene at all is quite beneficial," says Sellers. People lacking the CYP2A6 are less likely to become addicted to nicotine. On the other hand, people with more than two copies of the common CYP2A6 gene are susceptible to smoking heavily because they will process nicotine faster, and will need to smoke more to satisfy their addiction.

Another speaker at the conference, Neal Benowitz, of the University of California, San Francisco, presented work that addressed why Chinese have a lower rate of lung cancer than whites. Chinese tend to smoke fewer cigarettes than whites, and Benowitz found that they also metabolize nicotine more slowly. He is currently investigating whether this is due to a mutant CYP2A6 gene.

The CYP2A6 seems to be an evolutionary remnant that still survives in our genome today. People completely lacking the gene do not seem to experience side effects of any kind. Sellers suggests that perhaps the gene helped get rid of plant toxins early in evolution.

Both Benowitzís group and the team at University of Toronto are now looking at CYP2A6 genes in different ethnic groups to determine if some are more at risk for nicotine addiction.

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