GENE MUTATION HELPS SOME RESIST NICOTINE ADDICTION

Metabolism: Finding Could Help Smokers Quit; If Medicines Can Inhibit The
Breakdown Of Nicotine, Perhaps They Can Treat The Addiction.

Scientists have found that some people carry a genetic Lucky Strike: a
mutation that makes them feel lousy when they try their first cigarette --
and less likely to become addicted to nicotine.

The mutation, estimated to be carried by one-fifth of the non-smoking
population, impairs the ability to metabolize nicotine, the active
ingredient in tobacco products, said researcher Dr. Edward Sellers of the
University of Toronto.

New Target

The study offers a new target for developing more effective medicines to
help smokers quit. If medicines can inhibit the breakdown of nicotine, they
could prevent or treat the addiction.

``This in an interesting and important finding,'' said Dr. Alan I. Leshner,
director of the federal National Institute of Drug Abuse, which funded the
new study. ``Addiction is a brain disease. This study shows not only that
genetics are involved, but the mechanism through which genetics are acting.''

If people with the mutated gene persist in smoking, they need fewer
cigarettes to get the same satisfaction from nicotine as people without the
mutation, he said.

``They can become smokers, but they have to work really hard at it,'' said
Sellers.

The discovery, reported in today's issue of the journal Nature, helps
explain why some people are never attracted to smoking -- or if they do
smoke, why their addiction is mild and they can easily quit.

Nicotine, a plant product, is broken down by an enzyme in the liver called
CYP2A6. A defect in the gene that controls this enzyme interferes with the
metabolism of nicotine. The enzyme is thought to have been important
millions of years ago, when early mammals ate plants and needed help
metabolizing them.

The gene defect causes nicotine to be metabolized more slowly. For
first-time smokers, it exaggerates normal feelings of dizziness and nausea,
said Sellers.

Because nicotine sticks around longer in these people, they do not smoke as
much, or inhale as deeply, he said.

The new study is part of the investigation into the genetics of smoking
addiction, but is the first to identify an aversion to nicotine.

Previous research found a genetic variation that is linked to smoking at a
young age. That work by researchers at M.D. Anderson Cancer Center in
Houston found a gene that enhances the pleasurable feelings created by
nicotine. In a separate finding, scientists at the University of
California-San Francisco discovered that nicotine appears to stimulate
brain cells in nearly the same way cocaine does.

More Applications

Genetics also may explain other factors connected to drug abuse in general,
such as the origin of pleasure-seeking and stress-reducing behaviors. But
the latest discovery is particularly significant to solving the puzzle of
the biology of tobacco addiction.

``Individual people vary in their vulnerability to becoming addicted -- and
there is a large genetic component to this vulnerability,'' Leshner said.
``This study identifies a gene involved in these individual differences.''

The Toronto researchers found that 20 percent of non-smokers carry the
mutated version of the gene that regulates nicotine metabolism, compared
with 10 percent of smokers. They also found that smokers with the defective
gene smoked 20 percent fewer cigarettes a week.

``This gene is not complete protection. It's relative protection,'' said
Sellers.

The study also explains what some anti-smoking activists already have
observed.

``We know that some people have a much easier time quitting than others,''
said Margo Leathers, executive director of the American Lung Association of
Santa Clara County. ``Rarely, you hear of people who smoke only on
weekends, or only after dinner.

``But this news won't change the people who start smoking -- kids --
because they never think they'll become addicted.''

Cigarette smoking is responsible for one in five deaths in the United
States -- more than 400,000 deaths a year, according to the federal Centers
for Disease Control and Prevention. It accounts for 87 percent of all
American lung-cancer deaths.

California's Low Rate

In California, 18.7 percent of adults smoke, one of the lowest rates in the
nation.

Some medical experts worried that the news might take the pressure off the
tobacco industry by blaming biology, not marketing, for the smoking epidemic.

``It is a little bit scary if we adopt the view that humans emerged out of
the primordial slime with a smoking gene -- and 3 billion years later, Joe
Camel and the Marlboro cowboy have nothing to do with it,'' said
cardiologist Dr. Stan Glantz of UC-San Francisco.

Said Dr. John Slade, a professor of medicine at the University of New
Jersey School of Medicine: ``It could be something for tobacco companies to
hide behind. Nicotine still causes nicotine addiction.''

Checked-by: Richard Lake