title: Glucuronidation: an important mechanism for detoxification of benzo[a]pyrene metabolites in aerodigestive tract tissues.
abstract: UDP-glucuronosyltransferases (UGTs) have been implicated as important detoxifying enzymes for several major tobacco carcinogens. Because the aerodigestive tract is a primary target for exposure to tobacco smoke carcinogens, the major goal of the present study was to determine whether aerodigestive tract tissues exhibit glucuronidating activity against metabolites of benzo[a]pyrene (BaP) and to explore the pattern of expression of UGT genes in a series of aerodigestive tract tissue specimens. Glucuronidation of the phenolic BaP metabolites 3-, 7-, and 9-hydroxy-BaP was observed in all upper aerodigestive tract tissue microsome specimens tested, as determined by high-pressure liquid chromatography analysis. Glucuronidating activity toward the procarcinogenic BaP metabolite trans-BaP-7,8-dihydrodiol(+/-) was also detected in aerodigestive tract tissues. By semiquantitative duplex reverse transcription-polymerase chain reaction analysis, UGT1A7 and UGT1A10 were shown to be well expressed in all aerodigestive tract tissues examined, including tongue, tonsil, floor of mouth, larynx, and esophagus. UGT1A8 and UGT1A6 were expressed primarily in larynx; no expression was observed for UGTs 1A1, 1A3, 1A4, 1A5, 1A9. Of the family 2B UGTs, only UGT2B4 and UGT2B17 exhibited significant levels of expression in aerodigestive tract tissues. Of the aerodigestive tract-expressing UGTs, only UGTs 1A7, 1A8, and 1A10 exhibited glucuronidating activity against 7-hydroxy-BaP, with UGT1A10 exhibiting the highest affinity as determined by kinetic analysis (K(m) = 49 microM). No UGT expression or glucuronidating activity was observed for any of the lung specimens analyzed in this study. These results suggest that several family 1 UGTs may potentially play an important role in BaP detoxification in the aerodigestive tract.
authors.affiliation: Divisions of Cancer Control and Molecular Oncology, H. Lee Moffitt Cancer Center, Departments of Interdisciplinary Oncology, Biochemistry, and Pharmacology and Therapeutics, University of South Florida, Tampa, Florida 33612, USA.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zheng
authors.forename: Jia-Long
authors.initials: JL
authors.lastname: Fang
authors.forename: Philip
authors.initials: P
authors.lastname: Lazarus
mesh_terms: D001564:Benzo(a)pyrene / Q000031:analogs & derivatives / Q000378:metabolism* / Q000493:pharmacokinetics*; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D004064:Digestive System / Q000737:chemistry / Q000378:metabolism*; D004101:Dihydroxydihydrobenzopyrenes / Q000378:metabolism; D004947:Esophagus / Q000737:chemistry; D020719:Glucuronides / Q000096:biosynthesis* / Q000737:chemistry; D014453:Glucuronosyltransferase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008658:Inactivation, Metabolic; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D007830:Larynx / Q000737:chemistry; D008099:Liver / Q000737:chemistry; D008168:Lung / Q000737:chemistry; D008861:Microsomes / Q000737:chemistry / Q000378:metabolism; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D009055:Mouth / Q000737:chemistry; D009928:Organ Specificity / Q000235:genetics / Q000502:physiology; D014066:Palatine Tonsil / Q000737:chemistry; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D012137:Respiratory System / Q000737:chemistry / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014059:Tongue / Q000737:chemistry
chemical_list: D004101:Dihydroxydihydrobenzopyrenes; D020719:Glucuronides; D007527:Isoenzymes; D012333:RNA, Messenger; C017228:benzo(a)pyrene 7,8-dihydrodiol; D001564:Benzo(a)pyrene; D014453:Glucuronosyltransferase