Tobacco carcinogens influence Ah-receptor function
Abstracts
Initial Award Abstract |
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The etiology of lung, colon and bladder tumors still remains largely unknown. Recent epidemiological data from the American Cancer Society estimate that the greatest number of deaths related to these cancers will occur in the State of California. This may partially be because of population density, since California ranks 40th in the US for the estimated number of deaths per every 100,000 people. Studies show that individuals who consume tobacco products are at greater risk for the development of these tobacco-related cancers. Thus, the disruption of normal cellular and molecular mechanisms would appear to be targeted by ingredients in tobacco products, of which over 50 compounds have been shown to be carcinogenic in animal models.
Heterocyclic amines (HAs), present in tobacco smoke, are a group of compounds that cause colon and mammary tumors in rodents. Like most toxic agents, HAs are inert until they are converted by the body into new compounds capable of altering a cell’s programmable DNA, a process that eventually leads to tumorgenesis and malignancy. Enzymatic processes that participate in the metabolism of these agents are proteins called cytochrome P450s. The levels of P450s in the body are important as they are directly linked to the conversion of HAs to carcinogenic intermediates. The Ah receptor, a cytosolic protein, is an activator of transcription that increases the abundance of selective cytochrome P450s. Activation of the Ah receptor is a known prerequisite necessary to promote the metabolism of HAs to ultimate carcinogens. For example, tobacco carcinogens known as polycyclic aromatic hydrocarbons are activators of the Ah receptor and play a central role in tobacco carcinogen induced tumorgenesis.
PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine) is the most prevalent HA in tobacco smoke. Following exposure, PhIP undergoes oxidative metabolism by P450s to the carcinogenic intermediate N-OH-PhIP. In our laboratory, we have generated preliminary data to suggest that PhIP and N-OH-PhIP directly affect the transcriptional activity of selective P450 genes involved in carcinogen metabolism. PhIP appears to increase the levels of P450s presumably through the activation of the Ah receptor, whereas N-OH-PhIP is a potent inhibitor of the activation of the Ah receptor. The dual action of HAs on Ah receptor function may indicate a novel mechanism by which this protein controls cellular production of drug metabolizing enzymes. Thus, the goal of this proposal is to determine the cellular mechanisms by which HAs control Ah receptor function in the cell. Defining those pathways and the action of tobacco carcinogens on cellular functions are needed to clearly understand those events that underlie the etiology of tobacco-related cancers. |
