Ethnic and gender variation in nicotine detoxification
Initial Award Abstract
Lung cancer is the leading cause of cancer death in both men and women in the United States. The vast majority of lung cancer cases are related to tobacco smoking. The rate of detoxification of nicotine and nicotine-derived carcinogens is directly linked to the clearance of these compounds from the body and may play a critical role in individual susceptibility for tobacco-related cancer.
Glucuronidation is a metabolic pathway that plays a major role in the detoxification of many tobacco toxins. The rate of detoxification is determined by the availability of enzymes that can process these compounds, such as the UDP-glucuronosyltransferase (UGT) enzymes, and their functional activities. From the limited amount of available data, there appear to be ethnic and gender differences in the glucuronidation of nicotine and related chemicals. Some African-Americans detoxify nicotine slower than Caucasians, while the rate of glucuronidation is generally slower in women than in men. A reduction in the rate of glucuronidation may cause the accumulation of tobacco toxins in the body and lead to an elevated risk of cancer.
Nicotine, cotinine, and NNAL are major components of cigarette smoke that are responsible for causing tobacco-related lung cancer (NNAL) and for developing nicotine addictive behavior (nicotine and cotinine). We hypothesize that genetic variation in the UGT genes might explain the differences in the rates of nicotine, cotinine, and NNAL detoxification. In this clinical association study, we plan to investigate whether genetic differences in the relevant UGT genes would account for the known ethnic difference in glucuronidation rates between Caucasians, African-Americans, and Chinese-Americans. We also plan to investigate whether an association of variation in UGT genes and detoxification rates explains any of the difference in the rate of glucuronidation between women and men.
The aims of this proposed research are to: (1) identify new gene variants in the relevant glucuronidation enzyme (UGT) genes in three of California's major ethnic populations, Caucasian/Hispanics, African-Americans and Chinese-Americans; (2) determine the variation in UGT genes in 450 subjects from existing in vivo nicotine pharmacokinetics studies; and (3) assess whether variation in UGT genes correlate with individual differences in the rate of glucuronidation of nicotine, cotinine and NNAL. Statistical analyses will be used to compare the role that genetic variation plays in glucuronidation in these three ethnic groups. We will also analyze whether there are gender differences in the effects of genetic polymorphisms on nicotine glucuronidation.
The proposed research will improve our understanding of ethnic and gender differences in smoking-derived cancer risks. Evaluation of racial/ethnic variation in the molecular basis for detoxification of tobacco toxins may help identify an important contributor to the elevated risk of lung cancer in African-Americans. Gender-based analyses will help determine whether genotype-phenotype associations differ between women and men. Observed differences may account for increased cancer risks from tobacco smoking and from exposure to secondhand smoke. The results will help in designing education and prevention strategies targeting individuals at the highest risk of tobacco-related cancer. |