Xenobiotic Metabolism in Mice Lacking the UDP-Glucuronosyltransferase 2 Family
Xenobiotic Metabolism in Mice Lacking the UDP-Glucuronosyltransferase 2 Family
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DOI：
10.1124/dmd.115.065482
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发表时间：
2015-12-01
影响因子：
3.9
通讯作者：
Koller, Beverly H.
中科院分区：
文献类型：
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作者：
Fay, Matthew J.;My Trang Nguyen;Koller, Beverly H.
UDP-葡糖醛酸基转移酶（UGT）将葡糖醛酸的葡糖醛酸基与多种亲脂性底物结合，形成亲水性葡糖苷酸结合物。葡糖苷酸通常具有降低的生物活性和增加的水溶性以促进排泄。葡萄糖醛酸化是内源性废物和外源性物质（包括药物和有害工业化学品）的重要解毒途径。哺乳动物中存在两个具有临床意义的UGT酶家族：UGT 1和UGT 2。虽然这两个家族在基因结构上不同，但使用重组酶的研究表明，它们对许多底物的葡萄糖醛酸化能力存在相当大的重叠，这往往掩盖了这两个家族在体内清除特定底物方面的相对重要性。为了解决这一限制，我们已经产生了一个小鼠系，称为Δ Ugt 2，其中整个Ugt 2基因家族，超过609个酶对，被切除。该小鼠系提供了一种方法来确定两个UGT家族在体内的贡献。我们证明了这些动物的效用，首次定义的UGT 1和UGT 2家族的葡萄糖醛酸化的环境雌激素剂双酚A（BPA）的体内贡献。据报道，人类和啮齿动物UGT 2酶对该化学品的活性最高。令人惊讶的是，我们使用Delta Ugt 2小鼠的研究表明，虽然UGT 1和UGT 2亚型都可以结合BPA，但清除率在很大程度上取决于UGT 1。
UDP-Glucuronosyltransferases (UGTs) conjugate a glucuronyl group from glucuronic acid to a wide range of lipophilic substrates to form a hydrophilic glucuronide conjugate. The glucuronide generally has decreased bioactivity and increased water solubility to facilitate excretion. Glucuronidation represents an important detoxification pathway for both endogenous waste products and xenobiotics, including drugs and harmful industrial chemicals. Two clinically significant families of UGT enzymes are present in mammals: UGT1s and UGT2s. Although the two families are distinct in gene structure, studies using recombinant enzymes have shown considerable overlap in their ability to glucuronidate many substrates, often obscuring the relative importance of the two families in the clearance of particular substrates in vivo. To address this limitation, we have generated a mouse line, termed Delta Ugt2, in which the entire Ugt2 gene family, extending over 609 kilobase pairs, is excised. This mouse line provides a means to determine the contributions of the two UGT families in vivo. We demonstrate the utility of these animals by defining for the first time the in vivo contributions of the UGT1 and UGT2 families to glucuronidation of the environmental estrogenic agent bisphenol A (BPA). The highest activity toward this chemical is reported for human and rodent UGT2 enzymes. Surprisingly, our studies using the Delta Ugt2 mice demonstrate that, while both UGT1 and UGT2 isoforms can conjugate BPA, clearance is largely dependent on UGT1s.