: The long-term objective is to determine the role of respiratory tract cytochrome P450 (CYP) enzymes in target tissue metabolic activation and toxicity of environmental chemicals. Our focus is on human CYP2A13, which is highly active in the metabolic activation of several respiratory tract chemical carcinogens. Variations in CYP2A13 enzyme activity and/or expression in human tissues will likely influence the risks of chemical carcinogenesis associated with exposure to cigarette smoke or other CYP2A13-bioactivated substrates. This notion is strongly supported by data from epidemiological studies that demonstrate a significant association between a low-activity CYP2A13 allele (CYP2A13*2) and reduced incidences of smoking-induced lung adenocarcinoma. In our CA092596 grant, we are testing the hypotheses that (a) CYP2A13 provides an important metabolic activation pathway in human nasal and lung tissues to initiate chemical carcinogenesis, and (b) lung CYPs are responsible for xenobiotic-induced lung tumorigenesis in a novel knockout mouse model. The goal of this supplement is to determine the significance and the mechanistic basis of a newly discovered low expression phenotype associated with 7520G-containing CYP2A13 alleles. We found that transcripts from the 7520G-containing CYP2A13 alleles (primarily the *1X allele, which occurs in high frequency) are much less abundant than those from the 7520C-containing alleles. These unexpected findings present a unique opportunity for identifying genetic factors that influence CYP2A13 expression.
The aims for the supplement are:
Aim S1. To characterize the CYP2A13 haplotypes that are associated with decreased relative allelic expression in human lung.
Aim S2. To further characterize the low expression phenotype associated with the CYP2A13*1X allele. We will determine whether the low expression phenotype associated with the frequent *1X allele is tissue selective, and whether a *1X/*1X genotype correlates with significant decreases in CYP2A13 mRNA and protein levels in the lung or nasal mucosa.
Aim S3. To identify mechanisms underlying the low-CYP2A13 expression phenotype. We will measure relative allelic expression of CYP2A13 hnRNA, and determine whether the 7520C>G mutation in the 3'-untranslated region confers differing mRNA stability in transfected human lung cells. Our original aims remain unchanged. ? ?
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