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Nicotine pharmacogenetics: influence of ethnicity

Institution: Cedars-Sinai Medical Center
Investigator(s): Russell Poland, Ph.D.
Award Cycle: 1997 (Cycle 6) Grant #: 6RT-0069A Award: $242,344
Subject Area: Nicotine Dependence
Award Type: Research Project Awards

Final Report
It is well established that ethnicity can influence how the body breaks-down (metabolizes) different drugs. The differences in metabolism appear due, at least in part, to genes which control the expression of enzymes involved in metabolism. Recent information suggests that nicotine, the major compound in tobacco which accounts for the addictive component of smoking, is metabolized by an enzyme called CYP2A6, and that the activity of this enzyme appears to vary in different ethnic groups. The proposed study is designed to determine the influence of ethnicity on the metabolism of nicotine. Coumarin is being used as the metabolic probe to assess the status of CYP2A6. Cournarin metabolism was significantly reduced in smokers as compared to nonsmokers supporting in vitro studies that nicotine, cotinine and coumarin are metabolized, at least in part, by the same system. In addition, no difference was found in coumarin metabolism between Caucasians and MexicanAmericans, whereas coumarin metabolism was lower in African-Americans and Asians. We attempted to replicate this finding using a low-dose of nicotine (approx. 1.0 mg, oral) in non-smokers from the different ethnic groups. However, we were not able to show ethnic the differences in nicotine metabolism as we observed with coumarin. DNA has been extracted from blood samples obtained from African-American, Asian, Caucasian and Hispanic smokers and non-smokers and the samples have been genotyped for CYP2A6. We did not observe significant ethnic differences in the mutations for CYP2A6, although Asians tended to show more polymorphism. We also could not detect any relationship between coumarin or nicotine metabolism and mutations for CYP2A6 suggesting that other factors might be involved.