Nicotine regulates the expression of UDP-glucuronosyltransferase (UGT) in humanized UGT1 mouse brain.
Nicotine regulates the expression of UDP-glucuronosyltransferase (UGT) in humanized UGT1 mouse brain.
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DOI：
10.1016/j.dmpk.2015.04.004
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发表时间：
2015-08
影响因子：
2.1
通讯作者：
Fujiwara R
中科院分区：
文献类型：
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作者：
Sakamoto M;Itoh T;Tukey RH;Fujiwara R
UDP-葡萄糖醛酸基转移酶（UGT）是催化多种化合物葡萄糖醛酸化的酶家族，从而在大量外源性和内源性化合物的代谢和解毒中具有重要作用。 UGT 在肝脏和小肠中大量存在，而一些关于 UGT mRNA 定量的研究报告称 UGT 在大脑中也有表达。然而，所报道的人脑中 UGT 亚型的表达模式常常彼此不一致。因此，在本研究中，我们研究了人源化 UGT1 (hUGT1) 小鼠大脑中 UGT mRNA 的表达。我们发现人类UGT1成员中，UGT1A1、1A3和1A6在大脑中表达。我们进一步观察到尼古丁 (3 mg/kg) 诱导大脑中 UGT1A3 mRNA 的表达，但不诱导肝脏中的表达。虽然没有统计学意义，但尼古丁治疗导致脑微粒体中鹅去氧胆酸葡萄糖醛酸形成活性增加。 UGT1A3参与多种抗抑郁药和非甾体抗炎药的代谢，这些药物在大脑中发挥药理作用。因此，尼古丁治疗的 hUGT1 小鼠可能有助于研究大脑 UGT1A3 在调节这些药物的局部水平及其反应中的作用。
UDP-glucuronosyltransferase (UGT) is a family of enzymes that catalyze the glucuronidation of various compounds, and thereby has an important role in metabolism and detoxification of a large number of xenobiotic and endogenous compounds. UGTs are present highly in the liver and small intestine, while several investigations on quantification of UGT mRNA reported that UGTs were also expressed in the brain. However, reported expression patterns of UGT isoforms in human brain were often incongruous with each other. In the present study, therefore, we investigated UGT mRNA expressions in brains of humanized UGT1 (hUGT1) mice. We found that among the human UGT1 members, UGT1A1, 1A3, and 1A6 were expressed in the brain. We further observed that nicotine (3 mg/kg) induced the expression of UGT1A3 mRNA in the brain, but not liver. While it was not statistically significant, the nicotine treatment resulted in an increase in the chenodeoxycholic acid glucuronide-formation activity in the brain microsomes. UGT1A3 is involved in metabolism of various antidepressants and non-steroidal antiin-flammatory drugs, which exhibit their pharmacological effects in the brain. Therefore, nicotine-treated hUGT1 mice might be useful to investigate the role of brain UGT1A3 in the regulation of local levels of these drugs and their response.