Angela C. Chi, DMD
Project 2: CYP1B1 Induction in Tobacco-related Oral Carcinogenesis (Start date 7/1/07)
We are investigating the role of cytochrome p450 enzymes in tobacco-related oral carcinogenesis.
Tobacco use is a well-established, major risk factor for development of oral squamous cell carcinoma (SCC)--a disease that represents one of the ten leading cancers in men in the United States and is associated with major morbidity and mortality. Chief among the carcinogens in tobacco smoke are the polycyclic aromatic hydrocarbons, including benzo[a]pyrene (BP). Metabolic activation of PAHs by cytochrome p450 (CYP) enzymes leads to DNA adduct formation, which presumably leads to cancer development via interaction with genes essential for regulating key cell functions such as apoptosis, proliferation, and differentiation. In particular, p53 gene mutations are among the most frequent genetic anomalies identified in oral SCC, and BP metabolites are known to form adducts at specific "hotspots" within the p53 gene. Expression of CYP enzymes by extrahepatic tissues—including oral mucosa—is not well characterized. In human oral mucosa, the major CYP enzyme isoforms induced by exposure to BP appear to be CYP1A1 and CYP1B1, and preliminary studies by our laboratory suggest that in smokers there is preferential induction of CYP1B1 over CYP1A1. The specific aims of this proposal are as follows: 1) to test the hypothesis that preferential CYP1B1 induction occurs during smoking-related transformation of normal oral mucosa into epithelial dysplasia and SCC and 2) to test the hypothesis that CYP1B1 induction in oral mucosa leads to metabolic activation of BP, resulting in DNA adduct formation and p53 gene mutations. The proposed research will constitute the first rigorously quantitative investigation of CYP1B1 versus CYP1A1 expression in human oral tissues relative to tobacco exposure. Furthermore, our studies will begin to unravel the underlying mechanisms linking BP metabolite-DNA adduct formation to oral carcinogenesis by using in vitro oral tissue models to demonstrate CYP1B1 induction by BP leads to DNA adduct formation and mutations at specific sites within the p53 gene.