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January 15, 2002

Some Ethnic Differences in Lung Cancer Rates Linked to Nicotine Metabolism

Chinese-American smokers draw in less nicotine per cigarette
and also metabolize nicotine more slowly than Latinos and other
Caucasians, helping explain why they tend to smoke less than most
Caucasians and have relatively low rates of lung cancer, UCSF
scientists have found.

The finding supports growing evidence that ethnicity can
significantly affect people's response to drugs and should be
taken into account in developing and prescribing drugs, according
to the researchers.

The study is published in the January 16 issue of the Journal of
the National Cancer Institute.

The UCSF study found that Chinese-American smokers metabolize
nicotine at about two-thirds the rate of both Latinos and
non-Latino Caucasians, presumably keeping more nicotine in
their system per cigarette and satisfying their need for nicotine
with fewer cigarettes. In addition, the fact that they take in
less nicotine per cigarette than Latinos, other Caucasians -- and
African Americans -- means they also take in less of the other
compounds in cigarette smoke, including carcinogens.

While the slower nicotine metabolism and less intensive smoking
behavior found in the study may explain some of the known ethnic
differences in lung cancer rates, other factors must also be at
play, said Neal Benowitz, MD, UCSF professor of medicine,
psychiatry and biopharmaceutical sciences and lead author on the
JNCI paper. Benowitz is also leader of the Tobacco Control
Program of UCSF's Comprehensive Cancer Center.

Cancer researchers estimate that 90 percent of lung cancers are
caused by cigarette smoking. Caucasians in the U.S. are about
five times more likely to develop lung cancer from smoking than
are Chinese. Other possible reasons for lower lung cancer rates
in Chinese include the relatively late age at which they start
to smoke and their relatively higher rate of lung cancers not
related to smoking, Benowitz said.

The study also found that Latinos and non-Latino Caucasians
metabolize nicotine at about the same rate, supporting the view
that lower Latino lung cancer rates relative to non-Latino
Caucasians are due primarily to the fact that Latinos tend to
smoke fewer cigarettes, the researchers report.

In 1998, Benowitz and colleagues determined that African
Americans take in more nicotine and other smoke products
from cigarettes than Caucasians, primarily because they draw
more deeply on cigarettes when they smoke. The researchers think
this explains why African Americans have a greater incidence of
lung cancer than Caucasians despite the fact that the two smoke
about the same amount.

The researchers found a second metabolic difference that may
contribute to the lower incidence of lung cancer among Chinese
smokers. A liver enzyme known as CYP2A6 is primarily responsible
for metabolizing nicotine, the researchers note, and is also
involved in activating several carcinogens in tobacco smoke. The
study found lower CYP2A6 enzyme activity among Chinese-American

The lower lung cancer rate among Chinese and Chinese-Americans
is probably due in part to at least two factors uncovered by the
study: smoking fewer cigarettes per day -- related in part to
slower nicotine metabolism -- and dampened activity of
carcinogen-activating enzymes.

Understanding the ethnic differences in rates of nicotine
metabolism may be important in determining proper doses for
nicotine patches and other products to help smokers break the
habit, the scientists report. Clinical trials for these products
have been conducted primarily in the U.S. and Europe, with mostly
Caucasian participants, but China has more smokers than any other
country, with more than 300 million male and 20 million female
smokers. Nicotine doses in smoking cessation products may not be
optimal for them.

"Our findings suggest that Chinese-Americans and Chinese who are
trying to stop smoking may need a different dose of nicotine
medication than do Caucasians," Benowitz said.

Moreover, the scientists conclude, the findings reinforce the
growing awareness that ethnic differences in drug metabolism
should be evaluated as a matter of course in drug development,
prescribing and dosing.

In the study, 37 Chinese-American, 40 Latino and 54 non-Latino
Caucasian healthy volunteer smokers received simultaneous
infusions of deuterium-labeled nicotine and its metabolite,
cotinine. The researchers took blood and urine measurements
to study the daily intake and metabolism from smoking. The
labeled infusions were necessary to facilitate tracking the
metabolites, since smokers already have considerable levels of
nicotine and cotinine in their bodies that would make measurement
of metabolism and clearance of unlabeled compounds impossible.
Blood samples were taken frequently during the first day and then
every 24 hours up to four days after the infusions.

Co-authors on the paper and collaborators in the study are
Eliseo J. Perez-Stable, MD, UCSF professor of medicine; Brenda
Herrera, BS, research associate in clinical pharmacology at the
UCSF-affiliated San Francisco General Hospital Medical Center;
and Peyton Jacob, III, research chemist in psychiatry at UCSF.

The research is supported by the National Institutes of Health,
the National Cancer Institute and California's Tobacco Related
Disease Research Program.

by Wallace Ravven


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