LOS ANGELES, Mar 17 (Reuters Health) -- University of Toronto researchers are building a compelling case for the theory that smokers are hardwired to be nicotine-addicted. The latest evidence was presented here at the annual meeting of the American Societ

Dr. Rachel Tyndale and colleagues have demonstrated that a specific liver enzyme called cytochrome P450 2A6 metabolizes nicotine and also activates the cancer-causing substances found in tobacco smoke. A study of 400 smokers found that people with defective genes for the enzyme will smoke fewer cigarettes, Tyndale told Reuters Health in an interview. She explained that persons who are deficient in the enzyme metabolize nicotine very slowly, leading to less cigarettes smoked. Conversely, having extra copies of the gene that controls enzyme production, is associated with ``greater smoking frequency.'' Dr. Edward M. Sellers is senior investigator of the studies. Asked about the ``hardwired'' concept, Sellers said, ''ultimately everything is biologic and this is a fairly (distinct) enzyme.'' ``There is a difference of about 7 cigarettes a day between those with defective (liver enzyme genes) and those with extra copies,'' Tyndale explained. She said that difference, over 20 years, would be significant. In a small clinical trial of 11 patients, Tyndale and Sellers attempted to suppress the enzyme using the psoriasis drug methoxsalen. They used a relatively low dose of the medication, Tyndale said, so that the enzyme's activity level would be suppressed but with limited systemic effect. The dose was low enough, she added, so that ``the drug was virtually undetectable in (the bloodstream).'' The researchers theorized that enzyme inhibition would reduce the frequency of smoking. The five men and six women were given methoxsalen for 3 days and told to ``smoke normally,'' Tyndale said. After 3 days there was a decrease in breath carbon monoxide -- an index of smoke exposure -- as well as increased nicotine in the bloodstream. ``By suppressing the enzyme, we were able to keep nicotine levels up,'' Tyndale said. If nicotine levels are high, smokers don't experience the ``urge to smoke,'' she added. And, although the study subjects smoked the same number of cigarettes, ``the (carbon monoxide) measures indicate that they were smoking differently, they were taking fewer puffs or they were putting the cigarette out sooner,'' Sellers continued. Seller and Tyndale said the studies have important implications for treatment of smokers. For example, a cessation program that starts with ``three months of suppressing the enzyme and thus changing smoking behavior by decreasing frequency'' could be used a first step before putting a patient on ``nicotine patch or gum and total abstinence,'' Tyndale suggested. According to Seller, however, ``there is very little interest in programs that cut down on smoking. Cessation is the only recognized goal.'' In Tyndale's view, this bias is unfortunate because treatment of other illness, such as obesity does not require an all or nothing approach. No one insists that ``the patient lose every excess pound as the only acceptable treatment goal,'' she said. With obesity, the researcher noted, ``weight loss in any amount is encouraged.'' ``There is a graded health risk with exposure to smoke and although the data are not so clear when one goes back down the scale, there is no doubt that there is a health advantage to cutting back on cigarettes,'' Sellers commented. The studies were funded by the National Institute on Drug Addiction and Nicogen Inc., a biotech company that hold patents developed by Sellers and Tyndale.

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