Sakaguchi Kayo, Green Mitchell, Stock Nicholas, Reger Thomas S, Zunic Jasmine, King Christopher
Merck Research Laboratories, San Diego, 3535 General Atomics Court, San Diego, CA 92121, USA.
Arch Biochem Biophys. 2004 Apr 15;424(2):219-25. doi: 10.1016/j.abb.2004.02.004.
Glucuronide conjugation of xenobiotics containing a carboxylic acid moiety represents an important metabolic pathway for these compounds in humans. Several human UDP-glucuronosyltransferases (UGTs) have been shown to catalyze the formation of acyl-glucuronides, including UGT2B7, UGT1A3, and UGT1A9. In this study, recombinant expressed UGT isoforms were investigated with many structurally related carboxylic acid analogues, and the UGT rank order for catalyzing the glucuronidation of carboxylic acids was UGT2B7?UGT1A3 approximately UGT1A9. Despite being a poor substrate with UGT1A3, coumarin-3-carboxylic acid was not a substrate for any other UGT isoform tested in this study, suggesting that it could be a specific substrate for UGT1A3. Interestingly, UGT1A7 and UGT1A10 also react with several carboxylic acid aglycones. Kinetic analysis showed that UGT2B7 exhibits much higher glucuronidation efficiency (Vmax/Km) with ibuprofen, ketoprofen, and others, compared to UGT1A3. These data indicate that UGT2B7 could be the major isoform involved in the glucuronidation of carboxylic acid compounds in humans.
含有羧酸部分的外源性物质的葡萄糖醛酸结合反应是这些化合物在人体内的一条重要代谢途径。已证实几种人类尿苷二磷酸葡萄糖醛酸基转移酶（UGTs）可催化酰基葡萄糖醛酸的形成，包括UGT2B7、UGT1A3和UGT1A9。在本研究中，使用许多结构相关的羧酸类似物对重组表达的UGT同工型进行了研究，催化羧酸葡萄糖醛酸化反应的UGT排序为UGT2B7＞UGT1A3≈UGT1A9。尽管香豆素 - 3 - 羧酸是UGT1A3的不良底物，但它不是本研究中所测试的任何其他UGT同工型的底物，这表明它可能是UGT1A3的特异性底物。有趣的是，UGT1A7和UGT1A10也能与几种羧酸苷元发生反应。动力学分析表明，与UGT1A3相比，UGT2B7对布洛芬、酮洛芬及其他物质表现出更高的葡萄糖醛酸化效率（Vmax/Km）。这些数据表明UGT2B7可能是参与人类羧酸化合物葡萄糖醛酸化反应的主要同工型。
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