| This dissertation has laid the groundwork for understanding the physiological role of UGT2A enzymes in the local detoxification of PAH tobacco carcinogens. Results presented in this dissertation suggest that UGT2A1 is a major metabolizer of PAH carcinogens in the lung and other target tissues for tobacco carcinogenesis. UGT2A1 coding SNPs and a novel UGT2A1Aexon3 splice variant were characterized for the first time in this study. Results presented here suggest that the UGT2A1308Arg variant is associated with increased lung cancer risk, and we propose that inter-individual variability in UGT2A1Aexon3 expression may also impact cancer risk. Although additional work is needed to confirm these findings, results presented in this dissertation suggest that UGT2A1 variants negatively regulate wild-type UGT2A1 activity and may play a role in tobacco-related cancer susceptibility. (Abstract shortened by UMI.). |
