June 25, 1998 People with a common genetic defect that reduces their ability to metabolize nicotine are less likely to become smokers and, if they do smoke, will smoke fewer cigarettes, according to a University of Toronto study published in the June 25 issue of Nature.
"People with a defective gene are twice as likely to avoid smoking altogether," said Rachel Tyndale, an assistant professor in U of T's department of pharmacology and member of the biobehavioural research department at the Centre for Addiction and Mental Health. "In North America, where 30 per cent of the adult population smokes, this translates into about 7.5 million people who are protected against smoking by carrying a single copy of this gene defect."
Building on a study published last year in which they identified the gene CYP2A6 as responsible for most nicotine metabolism, Tyndale, along with co-investigator Edward Sellers and graduate student Michael Pianezza, found that 20 per cent of non-smokers carry a defective version of the gene, compared to only 10 per cent of smokers.
As well, since dependent smokers must adjust their smoking to maintain constant blood and brain nicotine levels, those with a defective gene resulting in impaired nicotine metabolism smoked an average of 129 cigarettes a week compared to the 159 cigarettes a week smoked by people without the defect -- a decrease of 20 per cent.
There are three types of the CYP2A6 gene: wild type (functioning) and two null alleles (defective). Individuals inherit two copies of this gene, one from their maternal and one from their paternal side. People who inherit two wild type genes have a fully functioning nicotine metabolism, while those carrying a wild type plus one of the null alleles have the defect. Less than one per cent of the population has two CYP2A6 null alleles.
The researchers studied two groups of people to determine if they had one or two copies of the defective gene: 184 people who had never smoked and 244 people who smoked regularly and had become tobacco dependent.
"With these findings comes the possibility of developing a method to chemically inhibit the function of the enzyme produced from the gene -- a prevention and treatment for tobacco smoking, in other words. That is the next step," said Sellers, a professor of pharmacology and medicine at U of T and director of the psychopharmacology and dependence research group at Women's College Hospital.
The researchers say there may also be implications for nicotine replacement therapies such as gum, patches and spray as some smokers will metabolize the nicotine in these therapies faster than others, altering their effectiveness. They also note that smokers who carry the defective gene will be less efficient at turning the procarcinogens in tobacco smoke into carcinogens, and may therefore, in addition to decreased smoking, be less likely to develop lung and other tobacco-related cancers.
Funding for the study was provided in part by the National Institutes on Drug Abuse (USA), Nicogen Research Inc., the University of Toronto and the Centre for Addiction and Mental Health.
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