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Vol. 30, Issue 4, 397-403, April 2002
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
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
(Km = 49 µM). 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.
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