QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: dmd.105.009100v1 34/6/943    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dellinger, R. W. Articles by Lazarus, P. Search for Related Content PubMed PubMed Citation Articles by Dellinger, R. W. Articles by Lazarus, P.

IMPORTANCE OF UDP-GLUCURONOSYLTRANSFERASE 1A10 (UGT1A10) IN THE DETOXIFICATION OF POLYCYCLIC AROMATIC HYDROCARBONS: DECREASED GLUCURONIDATIVE ACTIVITY OF THE UGT1A10^139LYS ISOFORM

Cancer Prevention and Control Program, Division of Population Sciences and Cancer Prevention, Penn State Cancer Institute (R.W.D., J.-L.F., G.C., R.W., P.L.), and Departments of Pharmacology (R.W.D., P.L.) and Health Evaluation Sciences (G.C., P.L.), Penn State University College of Medicine, Hershey, Pennsylvania

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 V_max/K_m 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 V_max could not be performed against family 2B UGTs, UGT1A10 exhibited a 1.7- to 254-fold lower K_m than active family 2B UGTs against 3-OH-BaP, 7-OH-BaP, and 1-OH-pyrene. A significantly (p < 0.01) higher V_max/K_m was observed for homogenates from wild-type UGT1A10^139Glu-overexpressing cells against all four BaP metabolites tested (3-OH-BaP, 7-OH-BaP, 9-OH-BaP, and BPD). A similarly significant (p < 0.05) increase in V_max/K_m was observed for homogenates from wild-type UGT1A10^139Glu-overexpressing cells against 1-OH-pyrene. Significant differences in K_m were observed for homogenates from wild-type UGT1A10^139Glu-overexpressing cells against 1-OH-pyrene (p < 0.05) and 3-OH-BaP (p < 0.01). Reverse transcription-polymerase chain reaction of total lung RNA showed low levels of UGT1A10 expression in human lung tissue. Together, these studies implicate UGT1A10 as an important detoxifier of polycyclic aromatic hydrocarbons in humans and that the UGT1A10 codon 139 polymorphism may be an important determinant in risk for tobacco-related cancers.

This article has been cited by other articles:

				G. Chen, R. W. Dellinger, D. Sun, T. E. Spratt, and P. Lazarus Glucuronidation of Tobacco-Specific Nitrosamines by UGT2B10 Drug Metab. Dispos., May 1, 2008; 36(5): 824 - 830. [Abstract] [Full Text] [PDF]

				D. Sun, A. K. Sharma, R. W. Dellinger, A. S. Blevins-Primeau, R. M. Balliet, G. Chen, T. Boyiri, S. Amin, and P. Lazarus Glucuronidation of Active Tamoxifen Metabolites by the Human UDP Glucuronosyltransferases Drug Metab. Dispos., November 1, 2007; 35(11): 2006 - 2014. [Abstract] [Full Text] [PDF]

				R. W. Dellinger, G. Chen, A. S. Blevins-Primeau, J. Krzeminski, S. Amin, and P. Lazarus Glucuronidation of PhIP and N-OH-PhIP by UDP-glucuronosyltransferase 1A10 Carcinogenesis, November 1, 2007; 28(11): 2412 - 2418. [Abstract] [Full Text] [PDF]

				G. Chen, A. S. Blevins-Primeau, R. W. Dellinger, J. E. Muscat, and P. Lazarus Glucuronidation of Nicotine and Cotinine by UGT2B10: Loss of Function by the UGT2B10 Codon 67 (Asp>Tyr) Polymorphism Cancer Res., October 1, 2007; 67(19): 9024 - 9029. [Abstract] [Full Text] [PDF]

				C. J. Gallagher, J. E. Muscat, A. N. Hicks, Y. Zheng, A.-M. Dyer, G. A. Chase, J. Richie, and P. Lazarus The UDP-Glucuronosyltransferase 2B17 Gene Deletion Polymorphism: Sex-Specific Association with Urinary 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol Glucuronidation Phenotype and Risk for Lung Cancer Cancer Epidemiol. Biomarkers Prev., April 1, 2007; 16(4): 823 - 828. [Abstract] [Full Text] [PDF]