Glucuronidation of drugs in humanized UDP-glucuronosyltransferase 1 mice: Similarity with glucuronidation in human liver microsomes.
Glucuronidation of drugs in humanized UDP-glucuronosyltransferase 1 mice: Similarity with glucuronidation in human liver microsomes.
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DOI：
10.1002/prp2.2
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发表时间：
2013-10
影响因子：
2.6
通讯作者：
Fujiwara, Ryoichi
中科院分区：
文献类型：
--
作者：
Kutsuno, Yuki;Sumida, Kyohei;Itoh, Tomoo;Tukey, Robert H;Fujiwara, Ryoichi
尿苷 5'-二磷酸-葡萄糖醛酸基转移酶 (UGT) 是 II 相药物代谢酶，可催化各种内源性和外源性底物的葡萄糖醛酸化。在 19 种功能性人类 UGT 中，UGT1A 家族酶主要参与临床药物的代谢。虽然 UGT1A 基因座在人类、小鼠和大鼠等哺乳动物中是保守的，但药物葡萄糖醛酸化的物种差异已被报道。最近，已经开发出人源化 UGT1 小鼠，其中原始 UGT1 基因座被破坏并被人 UGT1 基因座取代（hUGT1 小鼠）。为了评估 hUGT1 小鼠预测人类药物葡萄糖醛酸化的有用性，在 hUGT1 小鼠以及野生型小鼠和人类的肝微粒体中检查了 UGT 活性和对 UGT 的抑制作用。在 hUGT1 小鼠和人肝微粒体中，呋塞米酰基葡萄糖醛酸化呈 S 形，最适合 Hill 方程，而在小鼠肝微粒体中，它最适合底物抑制方程。 hUGT1 小鼠和人肝微粒体的呋塞米葡萄糖醛酸化动力学参数非常相似。 hUGT1肝微粒体中S-萘普生酰基葡萄糖醛酸化的动力学和化合物对呋塞米葡萄糖醛酸化的抑制作用也轻微，但与人肝微粒体中的相似，而不是在野生型小鼠中。虽然野生型小鼠缺乏丙咪嗪和三氟拉嗪 N-葡萄糖醛酸化潜力，但 hUGT1 小鼠表现出与人类相当的 N-葡萄糖醛酸化活性。我们的数据表明，hUGT1 小鼠是有前途的工具，不仅可以预测体内人类药物葡萄糖醛酸化，还可以预测潜在的药物间相互作用。
Uridine 5′-diphosphate-glucuronosyltransferases (UGTs) are phase II drug-metabolizing enzymes that catalyze glucuronidation of various endogenous and exogenous substrates. Among 19 functional human UGTs, UGT1A family enzymes largely contribute to the metabolism of clinically used drugs. While the UGT1A locus is conserved in mammals such as humans, mice, and rats, species differences in drug glucuronidation have been reported. Recently, humanized UGT1 mice in which the original Ugt1 locus was disrupted and replaced with the human UGT1 locus (hUGT1 mice) have been developed. To evaluate the usefulness of hUGT1 mice to predict human glucuronidation of drugs, UGT activities, and inhibitory effects on UGTs were examined in liver microsomes of hUGT1 mice as well as in those of wild-type mice and humans. Furosemide acyl-glucuronidation was sigmoidal and best fitted to the Hill equation in hUGT1 mice and human liver microsomes, while it was fitted to the substrate inhibition equation in mouse liver microsomes. Kinetic parameters of furosemide glucuronidation were very similar between hUGT1 mice and human liver microsomes. The kinetics of S-naproxen acyl-glucuronidation and inhibitory effects of compounds on furosemide glucuronidation in hUGT1 liver microsomes were also slightly, but similar to those in human liver microsomes, rather than in wild-type mice. While wild-type mice lack imipramine and trifluoperazine N-glucuronidation potential, hUGT1 mice showed comparable N-glucuronidation activity to that of humans. Our data indicate that hUGT1 mice are promising tools to predict not only in vivo human drug glucuronidation but also potential drug-drug interactions.