TY - JOUR T1 - UDP-glycosyltransferase 3A (UGT3A) metabolism of polycyclic aromatic hydrocarbons: potential importance in aerodigestive tract tissues JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.119.089284 SP - dmd.119.089284 AU - Ana G. Vergara AU - Christy J.W. Watson AU - Gang Chen AU - Philip Lazarus Y1 - 2019/01/01 UR - http://dmd.aspetjournals.org/content/early/2019/12/17/dmd.119.089284.abstract N2 - Polycyclic aromatic hydrocarbons (PAHs) are potent carcinogens and are a primary risk factor in the development of lung and other aerodigestive tract cancers in smokers. The detoxification of PAHs by glucuronidation is well-characterized for the UDP-glycosyltransferase (UGT) 1A, 2A, and 2B subfamilies; however, the role of the UGT3A subfamily in PAH metabolism remains poorly understood. UGT3A enzymes are functionally distinct from other UGT subfamilies (which utilize UDP-glucuronic acid as cosubstrate) due to their utilization of alternative cosubstrates (UDP-N-acetylglucosamine for UGT3A1, and UDP-glucose and UDP-xylose for UGT3A2). The goal of the present study was to characterize UGT3A glycosylation activity against PAHs and examine their expression in human aerodigestive tract tissues. In vitro metabolism assays using UGT3A2-overexpressing cell microsomes indicated that UGT3A2 exhibits glycosylation activity against all of the simple and complex PAHs tested. The Vmax/Km ratios for UGT3A2 activity with UDP-xylose vs. UDP-glucose as cosubstrate ranged from 0.71-4.0 for all PAHs tested, demonstrating that PAH glycosylation may be occurring at rates up to four-fold higher with UDP-xylose than UDP-glucose. Limited glycosylation activity was observed against PAHs with UGT3A1-overexpressing cell microsomes. While UGT3A2 exhibited low levels of hepatic expression, it was shown by Western blot analysis to be widely expressed in aerodigestive tract tissues. Conversely, UGT3A1 exhibited highest expression in liver with lower expression in aerodigestive tract tissues. These data suggest that UGT3A2 plays an important role in the detoxification of PAHs in aerodigestive tract tissues, and that there may be cosubstrate dependent differences in the detoxification of PAHs by UGT3A2.SIGNIFICANCE STATEMENT UGT3A2 is highly active against PAHs with either UDP-glucose or UDP-xylose as a cosubstrate. UGT3A1 exhibited low levels of activity against PAHs. UGT3A1 is highly expressed in liver while UGT3A2 is well-expressed in extra-hepatic tissues. UGT3A2 may be an important detoxifier of PAHs in humans. ER -