OBJECTIVE: To examine UGT2A1 expression in human tissues, determine its glucuronidation activity against tobacco carcinogens, and assess the potential functional role of UGT2A1 missense single nucleotide polymorphisms on UGT2A1 enzyme activity. METHODS: Reverse transcription polymerase chain reaction and real time polymerase chain reaction were used to assess UGT2A1 gene expression in various human tissues. A glucuronidation assay measured by reverse phase ultra-performance liquid chromatography was used to determine UGT2A1 activity. RESULTS: UGT2A1 was expressed in aerodigestive tract tissues including trachea, larynx, tonsil, lung, and colon; no expression was observed in breast, whole brain, pancreas, prostate, kidney, liver, or esophagus. UGT2A1 exhibited highest expression in the lung, followed by trachea >tonsil >larynx >colon >olfactory tissue. Cell homogenates prepared from wildtype UGT2A1(75Lys308Gly) overexpressing HEK293 cells showed significant glucuronidation activity against a variety of polycyclic aromatic hydrocarbons including, 1-hydroxy-benzo(a)pyrene, benzo(a)pyrene-7,8-diol, and 5-methylchrysene-1,2-diol. No activity was observed in UGT2A1 overexpressing cell homogenate against substrates that form N-glucuronides, such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), nicotine, or N-OH-2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (N-OH PhIP). A significant (P<0.05) decrease (approximately 25%) in glucuronidation activity (Vmax/KM) was observed against all polycyclic aromatic hydrocarbons substrates for the UGT2A1(75Lys308Gly) variant compared with homogenates from wildtype UGT2A1(75Lys308Gly); no activity was observed for cell homogenates overexpressing the UGT2A1 variant for all substrates tested. CONCLUSION: These data suggest that UGT2A1 is an important detoxification enzyme in the metabolism of polycyclic aromatic hydrocarbons within target tissues for tobacco carcinogens and functional polymorphisms in UGT2A1 may play a role in tobacco-related cancer risk.
OBJECTIVE: To exn>an class="Chemical">amineUGT2A1 expression in human tissues, determine its glucuronidation activity against tobacco carcinogens, and assess the potential functional role of UGT2A1 missense single nucleotide polymorphisms on UGT2A1 enzyme activity. METHODS: Reverse transcription polymerase chain reaction and real time polymerase chain reaction were used to assess UGT2A1 gene expression in various human tissues. A glucuronidation assay measured by reverse phase ultra-performance liquid chromatography was used to determine UGT2A1 activity. RESULTS:UGT2A1 was expressed in aerodigestive tract tissues including trachea, larynx, tonsil, lung, and colon; no expression was observed in breast, whole brain, pancreas, prostate, kidney, liver, or esophagus. UGT2A1 exhibited highest expression in the lung, followed by trachea >tonsil >larynx >colon >olfactory tissue. Cell homogenates prepared from wildtype UGT2A1(75Lys308Gly) overexpressing HEK293 cells showed significant glucuronidation activity against a variety of polycyclic aromatic hydrocarbons including, 1-hydroxy-benzo(a)pyrene, benzo(a)pyrene-7,8-diol, and 5-methylchrysene-1,2-diol. No activity was observed in UGT2A1 overexpressing cell homogenate against substrates that form N-glucuronides, such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), nicotine, or N-OH-2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (N-OH PhIP). A significant (P<0.05) decrease (approximately 25%) in glucuronidation activity (Vmax/KM) was observed against all polycyclic aromatic hydrocarbons substrates for the UGT2A1(75Lys308Gly) variant compared with homogenates from wildtype UGT2A1(75Lys308Gly); no activity was observed for cell homogenates overexpressing the UGT2A1 variant for all substrates tested. CONCLUSION: These data suggest that UGT2A1 is an important detoxification enzyme in the metabolism of polycyclic aromatic hydrocarbons within target tissues for tobacco carcinogens and functional polymorphisms in UGT2A1 may play a role in tobacco-related cancer risk.
Authors: Hugo Girard; Lesley M Butler; Lyne Villeneuve; Robert C Millikan; Rashmi Sinha; Robert S Sandler; Chantal Guillemette Journal: Mutat Res Date: 2008-07-16 Impact factor: 2.433
Authors: Dongxiao Sun; Arun K Sharma; Ryan W Dellinger; Andrea S Blevins-Primeau; Renee M Balliet; Gang Chen; Telih Boyiri; Shantu Amin; Philip Lazarus Journal: Drug Metab Dispos Date: 2007-07-30 Impact factor: 3.922
Authors: Michael J Miley; Agnieszka K Zielinska; Jeffrey E Keenan; Stacie M Bratton; Anna Radominska-Pandya; Matthew R Redinbo Journal: J Mol Biol Date: 2007-03-30 Impact factor: 5.469
Authors: Katriina Itäaho; Peter I Mackenzie; Shin-ichi Ikushiro; John O Miners; Moshe Finel Journal: Drug Metab Dispos Date: 2008-08-21 Impact factor: 3.922
Authors: Ryan W Dellinger; Gang Chen; Andrea S Blevins-Primeau; Jacek Krzeminski; Shantu Amin; Philip Lazarus Journal: Carcinogenesis Date: 2007-07-17 Impact factor: 4.944
Authors: Shannon Kozlovich; Gang Chen; Christy J W Watson; William J Blot; Philip Lazarus Journal: Drug Metab Dispos Date: 2019-10-02 Impact factor: 3.922
Authors: Steven G Carmella; Xun Ming; Natalie Olvera; Claire Brookmeyer; Andrea Yoder; Stephen S Hecht Journal: Chem Res Toxicol Date: 2013-07-24 Impact factor: 3.739
Authors: Kristine C Olson; Dongxiao Sun; Gang Chen; Arun K Sharma; Shantu Amin; Ira J Ropson; Thomas E Spratt; Philip Lazarus Journal: Chem Res Toxicol Date: 2011-08-05 Impact factor: 3.739
Authors: Moshe Shike; Ashley S Doane; Lianne Russo; Rafael Cabal; Jorge S Reis-Filho; William Gerald; Hiram Cody; Raya Khanin; Jacqueline Bromberg; Larry Norton Journal: J Natl Cancer Inst Date: 2014-09-04 Impact factor: 13.506