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 smokers.

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.