Glucuronidation: an important mechanism for detoxification of benzo[a]pyrene metabolites in aerodigestive tract tissues.
Glucuronidation: an important mechanism for detoxification of benzo[a]pyrene metabolites in aerodigestive tract tissues.
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DOI：
10.1124/dmd.30.4.397
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发表时间：
2002-04
期刊：
影响因子：
--
通讯作者：
Zhong Zheng;Jia-Long Fang;P. Lazarus
中科院分区：
文献类型：
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作者：
Zhong Zheng;Jia-Long Fang;P. Lazarus
UDP-葡萄糖醛酸基转移酶（UGT）被认为是几种主要烟草致癌物的重要解毒酶。由于呼吸消化道是暴露于烟草烟雾致癌物的主要目标，本研究的主要目标是确定呼吸消化道组织是否对苯并[a]芘（BaP）的代谢产物表现出葡萄糖醛酸化活性，并探讨UGT基因在一系列呼吸消化道组织标本中的表达模式。通过高压液相色谱分析测定，在所有上呼吸消化道组织微粒体样本中均观察到苯并（a）芘酚代谢产物3-、7-和9-羟基-苯并（a）芘的葡萄糖醛酸化。在呼吸消化道组织中也检测到对前致癌BaP代谢物trans-BaP-7，8-dihydrodiol（+/-）的葡萄糖醛酸化活性。通过半定量双链逆转录-聚合酶链反应分析，显示UGT 1A 7和UGT 1A 10在检查的所有呼吸消化道组织中表达良好，包括舌、扁桃体、口底、喉和食管。UGT 1A 8和UGT 1A 6主要在喉部表达;未观察到UGT 1A 1、1A 3、1A 4、1A 5、1A 9的表达。在家族2B UGT中，仅UGT 2B 4和UGT 2B 17在呼吸消化道组织中表现出显著水平的表达。在呼吸消化道表达的UGT中，仅UGT 1A 7、1A 8和1A 10表现出对7-羟基-BaP的葡萄糖醛酸化活性，通过动力学分析测定，UGT 1A 10表现出最高的亲和力（K（m）= 49 μ M）。在本研究中分析的任何肺标本中均未观察到UGT表达或葡萄糖醛酸化活性。这些结果表明，几个家庭1 UGT可能发挥重要作用，苯并[a]芘解毒在呼吸消化道。
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.