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The role of P450s in tobacco-mediated lung cancer

Institution: California Toxicology Research Institute
Investigator(s): Scott Allen, M.S., Ph.D.
Award Cycle: 2001 (Cycle 10) Grant #: 10KT-0202A Award: $295,815
Subject Area: Cancer
Award Type: New Investigator Awards

Initial Award Abstract
Lung cancer is the leading cause of cancer mortality in both men and women in the U.S. A major cause of lung cancer is tobacco smoking. Thus, cigarette smoking is a major health issue which must be addressed. As the addictive agent that prevents smokers from quitting, nicotine is a major cause of human cancers. Although nicotine itself is not carcinogenic, derivatives of nicotine and other nicotine metabolites are carcinogenic. A better understanding of nicotine and tobacco-related carcinogens would provide a means for determining the mechanisms by which tobacco use causes disease. The cytochrome P450 (P450) are a multi-gene family of oxidative enzymes. The primary role of P450s is the deactivation of a wide range of drugs and foreign compounds called xenobiotics. These include the tobacco constituents nicotine and nitrosamines. In order for nitrosamines to cause cancer, they must be activated by P450 enzymes. P450 enzymes in the liver are known to metabolize and activate nicotine and nitrosamines to procarcinogens, but the role of P450s in the lungs are not as well understood. The overall goal of this proposal is to study the P450s involved in nicotine and nitrosamine metabolism in human lung and their role in tobacco-mediated lung cancer. This project is using a variety of scientific techniques to determine which P450s in the lungs are involved in nicotine breakdown.

In the second year of this grant, we have identified several P450s expressed in human lungs. These P450s are currently being studied further to determine if their levels are increased by exposure to nicotine and other constituents of tobacco smoke. We have also cultured a human lung cell line that we can use in the laboratory as a model of human lung cells that are exposed to tobacco smoke. Furthermore, we have isolated regulatory regions of a P450 gene and are currently identifying the region of the gene responsible for activation by nicotine and other tobacco constituents. This will allow us to study, in the laboratory, the effects of tobacco smoke on specific P450s in the human lung.

As this project continues, the specific region of a P450 gene involved in tobacco activation should be identified. This should lead to a better understanding of P450s, the enzymes that breakdown nicotine and other tobacco constituents. In turn, this can lead to a better understanding of tobacco-mediated lung cancer in humans. Furthemore, this research can establish a basis for improved and novel therapeutic approaches to the treatment of tobacco addiction and other tobacco-related diseases.