Importance of UDP-glucuronosyltransferase 1A10 (UGT1A10) in the detoxification of polycyclic aromatic hydrocarbons: decreased glucuronidative activity of the UGT1A10139Lys isoform

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Ryan W DellingerPhilip Lazarus

Abstract

UDP-glucuronosyltransferase 1A10 (UGT1A10) is an extrahepatic enzyme expressed in aerodigestive tract tissues that exhibits significant glucuronidation activity against the important procarcinogenic benzo(a)pyrene (BaP) metabolite, BaP-trans-7,8-dihydrodiol (BPD), and the UGT1A10 codon 139 (Glu>Lys) polymorphism was previously implicated in risk for orolaryngeal cancer by Elahi et al. in their 2003 study. To better assess the potential role of UGT1A10 in risk for tobacco-related cancers, the glucuronidation activity of UGT1A10 was compared with that of other known UGT enzymes against selected polycyclic aromatic hydrocarbons, and the effects of the codon 139 polymorphism on UGT1A10 function were examined in vitro. UGT1A10 exhibited considerably more glucuronidation activity as determined by Vmax/Km against 3-hydroxy (OH)-BaP, 7-OH-BaP, 9-OH-BaP, and 1-OH-pyrene than any other UGT1A family member. Although a kinetic comparison using Vmax could not be performed against family 2B UGTs, UGT1A10 exhibited a 1.7- to 254-fold lower Km than active family 2B UGTs against 3-OH-BaP, 7-OH-BaP, and 1-OH-pyrene. A significantly (p < 0.01) higher Vmax/Km was observed for homogenates from wild-type UGT1A10139Glu-overexpressing cells against al...Continue Reading

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Citations

Apr 26, 2012·Chemical Research in Toxicology·Slobodan Rendic, F Peter Guengerich
Apr 17, 2012·Toxicological Sciences : an Official Journal of the Society of Toxicology·Alexander P SobinoffEileen A McLaughlin
Jan 10, 2012·Pharmacogenetics and Genomics·Gang ChenPhilip Lazarus
Feb 2, 2008·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Gang ChenPhilip Lazarus
Jul 11, 2009·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Kristine C OlsonPhilip Lazarus
Oct 30, 2010·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Jin ZhouRory P Remmel
Oct 23, 2012·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Ryan T BusheyPhilip Lazarus
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Oct 10, 2015·Chemical Research in Toxicology·Shannon KozlovichPhilip Lazarus
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Apr 10, 2007·Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology·Carla J GallagherPhilip Lazarus

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