3'-azido-3'-deoxythimidine (AZT) is glucuronidated by human UDP-glucuronosyltransferase 2B7 (UGT2B7).
3'-azido-3'-deoxythimidine (AZT) is glucuronidated by human UDP-glucuronosyltransferase 2B7 (UGT2B7).
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发表时间：
2000-05
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通讯作者：
O. Barbier;D. Turgeon;C. Girard;Mitchell D. Green;T. Tephly;D. Hum;A. Bélanger
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作者：
O. Barbier;D. Turgeon;C. Girard;Mitchell D. Green;T. Tephly;D. Hum;A. Bélanger
3 '-叠氮基-3'-脱氧胸苷（AZT）经常用于人类免疫缺陷病毒感染患者。吸收后，AZT通过UDP-葡萄糖醛酸转移酶（UGT）迅速代谢为3 '-叠氮基-3'-脱氧-5 '-葡萄糖醛酸胸苷。使用稳定表达不同人UGT 2B同工酶的人肾293细胞的标记[（14）C] UDP-葡萄糖醛酸和微粒体制备物，证明人UGT 2B 7特异性催化AZT葡萄糖醛酸化。通过液相色谱-质谱联用确认所形成的代谢产物为AZT-G。UGT 2B 7由多态性基因编码，通过两种等位基因变体UGT 2B 7（H（268））和UGT 2B 7（Y（268））进行的AZT葡萄糖醛酸化动力学分析得出表观K（m）值分别为91.0和80.1 microM。标准化至蛋白质水平得到葡萄糖醛酸化效率比（V（max）/K（m））为21.3和11.0 μ l。min（-1）。对于UGT 2B 7（H（268））和UGT 2B 7（Y（268）），分别为mg蛋白（-1）。其他UGT酶也可能参与AZT结合;然而，UGT 2B 7（一种在肝脏中表达的UGT 2B蛋白）对AZT的葡萄糖醛酸化与先前的发现一致，并支持该酶在AZT结合中的生理相关性。
3'-Azido-3'-deoxythymidine (AZT) is frequently prescribed to patients infected with the human immunodeficiency virus. After absorption, AZT is rapidly metabolized into 3'-azido-3'-deoxy-5'-glucuronylthymidine by UDP-glucuronosyltransferase (UGT) enzymes. Using labeled [(14)C]UDP-glucuronic acid and microsomal preparations from human kidney 293 cells stably expressing the different human UGT2B isoenzymes, it was demonstrated that AZT glucuronidation is catalyzed specifically by human UGT2B7. The identity of the metabolite formed was confirmed as AZT-G by liquid chromatography coupled with mass spectrometry. UGT2B7 is encoded by a polymorphic gene and kinetic analysis of AZT glucuronidation by the two allelic variants UGT2B7(H(268)) and UGT2B7(Y(268)), yielded apparent K(m) values of 91.0 and 80.1 microM, respectively. Normalization to protein levels yielded glucuronidation efficiency ratios (V(max)/K(m)) of 21.3 and 11.0 microl. min(-1). mg protein(-1) for UGT2B7(H(268)) and UGT2B7(Y(268)), respectively. It remains possible that other UGT enzymes are also involved in AZT conjugation; however, the glucuronidation of AZT by UGT2B7, which is a UGT2B protein expressed in the liver, is consistent with previous findings and supports the physiological relevance of this enzyme in AZT conjugation.