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The role of P450s in tobacco-mediated lung cancer

Institution: La Jolla Institute for Molecular Medicine
Investigator(s): Scott Allen, M.S., Ph.D.
Award Cycle: 2001 (Cycle 10) Grant #: 10KT-0202 Award: $147,858
Subject Area: Cancer
Award Type: New Investigator Awards

Initial Award Abstract
Smoking is a chronic condition that affects more than 46 million Americans. People who smoke are at risk for many diseases including heart disease, cancer, and other smoking-related illnesses. Together, treatment of these diseases costs more than $50 billion annually and an additional $47 billion in indirect costs from lost time at work and disability. Thus, cigarette smoking is a major health issue which must be addressed.

Cigarette smoke contains many compounds including nicotine. 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 carcinogens. 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 (P450s) are a multi-gene family of oxidative enzymes. The primary role of P450s is the deactivation of a wide range of drugs and 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. The proposed grant application will use a variety of scientific techniques to determine which P450s in the lungs are involved in nicotine breakdown.

Nicotine metabolites are generated in humans not only from tobacco smoke, but also from the use of nicotine replacement medications (ie. patch, gum, inhalers, etc.) that are used to help people stop smoking. Thus, the treatment for smoking (the use of these medications) supplies people with nicotine, which can also be converted to cancer-causing nitrosamines. Thus, the treatment for tobacco addiction can also cause cancer.

A better understanding of P450s, the enzymes that break down nicotine, can lead to a better understanding of tobacco-mediated lung cancer. Furthermore, this research can establish a basis for improved and novel therapeutic approaches to the treatment of tobacco addiction and other tobacco-related diseases.