A major goal of our laboratory has been the elucidation of the role of the human cytochrome P450, CYP1A1, in lung carcinogenesis. The protein product of the CYP1A1 gene and its associated catalytic activities, including aryl (or aromatic) hydrocarbon hydroxylase (AHH), are known to be intimately associated with the metabolic activation of numerous procarcinogenic polycyclic aromatic hydrocarbons (PAHs) found in cigarette smoke and other environmental pollutants to highly reactive intermediates. Numerous studies have reported a significant correlation between this phenotype and an enhanced susceptibility to lung cancer in cigarette smokers. 1) Determination of the molecular mechanisms responsible for expression of the human CYP1A1 gene. Induction of CYP1A1 gene expression is mediated through the action of the Ah receptor (AhR). There are at least five candidate binding sites for the AhR within the regulatory region of the CYP1A1 gene, and we have carried out a detailed functional analysis of each. By this procedure we have identified a unique mechanism for the expression of the CYP1A1 gene. 2) Identification of novel polymorphisms of the gene encoding the ligand-binding subunit of the Ah receptor (AhR). We have undertaken the task of identifying polymorphisms within genes associated with the regulation of CYP1A1 gene expression. We recently published the identification of an MspI restriction fragment length polymorphism (RFLP) of the AhR. DNAs from age, race, and sex matched controls and histologically confirmed lung cancer patients were examined to determine the frequency of the newly acquired genetic marker within the two populations. The polymorphic allele was present in 67% of the control population and absent in 33%. In the lung cancer population, the polymorphic allele was present in 53% of the individuals examined and absent in the remaining 47%. We have determined that the absence of the polymorphic allele is a factor associated with increased lung cancer risk (OR 2.45). Preliminary data also suggest that there are gender and race differences in the frequency of the polymorphism. Further characterization of this polymorphism is in progress.
