Species differences in drug glucuronidation: Humanized UDP-glucuronosyltransferase 1 mice and their application for predicting drug glucuronidation and drug-induced toxicity in humans.
Species differences in drug glucuronidation: Humanized UDP-glucuronosyltransferase 1 mice and their application for predicting drug glucuronidation and drug-induced toxicity in humans.
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DOI：
10.1016/j.dmpk.2017.10.002
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发表时间：
2018-03
影响因子：
2.1
通讯作者：
Tukey RH
中科院分区：
文献类型：
--
作者：
Fujiwara R;Yoda E;Tukey RH
超过20%的临床使用药物是通过微粒体酶UDP-葡萄糖醛酸基转移酶(UGT)进行葡萄糖醛酸化的。抑制或诱导UGT可导致血药浓度升高或降低。因此，为了避免药物间相互作用和个体药物不良反应，了解 UGT 是否参与药物和候选药物的代谢非常重要。虽然大多数葡萄糖醛酸苷是无活性的代谢物，但由带有羧酸基团的化合物形成的酰基葡萄糖苷酸可能具有剧毒。小鼠和大鼠等动物被广泛用于预测人类的药物代谢和药物引起的毒性。然而，包括 UGT 在内的药物代谢酶的表达和功能存在明显的物种差异。为了克服物种差异，最近开发了某些药物代谢酶人源化的小鼠。人源化 UGT1 (hUGT1) 小鼠于 2010 年通过在 C57BL/6 背景下将 Ugt1 缺失小鼠与人 UGT1 转基因小鼠杂交而创建。 hUGT1 小鼠可能成为预测人类药物葡萄糖醛酸化和酰基葡萄糖醛酸相关毒性的有前途的工具。在这篇综述文章中，总结了 hUGT1 小鼠的药物代谢和毒性研究。我们进一步讨论研究和战略方向，以增进对人类药物葡萄糖醛酸化的理解。
More than 20% of clinically used drugs are glucuronidated by a microsomal enzyme UDP-glucuronosyltransferase (UGT). Inhibition or induction of UGT can result in an increase or decrease in blood drug concentration. To avoid drug-drug interactions and adverse drug reactions in individuals, therefore, it is important to understand whether UGTs are involved in metabolism of drugs and drug candidates. While most of glucuronides are inactive metabolites, acyl-glucuronides that are formed from compounds with a carboxylic acid group can be highly toxic. Animals such as mice and rats are widely used to predict drug metabolism and drug-induced toxicity in humans. However, there are marked species differences in the expression and function of drug-metabolizing enzymes including UGTs. To overcome the species differences, mice in which certain drug-metabolizing enzymes are humanized have been recently developed. Humanized UGT1 (hUGT1) mice were created in 2010 by crossing Ugt1-null mice with human UGT1 transgenic mice in a C57BL/6 background. hUGT1 mice can be promising tools to predict human drug glucuronidation and acyl-glucuronide-associated toxicity. In this review article, studies of drug metabolism and toxicity in the hUGT1 mice are summarized. We further discuss research and strategic directions to advance the understanding of drug glucuronidation in humans.
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影响因子：
4.6
作者：
Aoshima N;Fujie Y;Itoh T;Tukey RH;Fujiwara R
通讯作者：
Fujiwara R
影响因子：
2.1
作者：
Fujiwara, Ryoichi;Itoh, Tomoo
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影响因子：
6.4
作者：
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通讯作者：
OVERVIK, E
影响因子：
3.9
作者：
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通讯作者：
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