Role of CYP2A6 in Methimazole Bioactivation and Hepatotoxicity.
Role of CYP2A6 in Methimazole Bioactivation and Hepatotoxicity.
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DOI：
10.1021/acs.chemrestox.1c00300
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发表时间：
2021-12-20
影响因子：
4.1
通讯作者：
Ma X
中科院分区：
文献类型：
--
作者：
Li J;Hussain Z;Zhu J;Lei S;Lu J;Ma X
甲巯咪唑（Methimazole， MMI）是一种应用广泛的抗甲状腺药物，但其引起肝毒性的机制尚不清楚。既往研究表明，MMI的肝脏代谢产生n -甲基硫脲导致肝损伤。然而，负责产生有毒代谢物n -甲基硫脲的特定酶仍不清楚。在这项研究中，我们筛选了MMI生产n -甲基硫脲的细胞色素P450 （CYPs）。CYP2A6被认为是催化MMI代谢生成n -甲基硫脲的关键酶。当用CYP2A6抑制剂预处理小鼠时，MMI形成的n -甲基硫脲明显减少。与此一致，CYP2A6抑制剂可阻止mmi诱导的肝毒性。这些结果表明CYP2A6在MMI的生物激活和肝毒性中是必不可少的。
Methimazole (MMI) is a widely used antithyroid drug, but it can cause hepatotoxicity by unknown mechanisms. Previous studies showed that hepatic metabolism of MMI produces N-methylthiourea leading to liver damage. However, the specific enzyme responsible for the production of the toxic metabolite N-methylthiourea is still unclear. In this study, we screened cytochromes P450 (CYPs) in N-methylthiourea production from MMI. CYP2A6 was identified as the key enzyme in catalyzing MMI metabolism to produce N-methylthiourea. When mice were pretreated with a CYP2A6 inhibitor, formation of N-methylthiourea from MMI was remarkably reduced. Consistently, the CYP2A6 inhibitor prevented MMI-induced hepatotoxicity. These results demonstrated that CYP2A6 is essential in MMI bioactivation and hepatotoxicity.
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影响因子：
--
作者：
Tanner JA;Tyndale RF
通讯作者：
Tyndale RF
影响因子：
5.8
作者：
ARAB, DM;MALATJALIAN, DA;RITTMASTER, RS
通讯作者：
RITTMASTER, RS
影响因子：
0.3
作者：
Chen, Wei-Che;Zhu, Zheng-Xin;Chien, Ming-Nan
通讯作者：
Chien, Ming-Nan
DOI：
10.1016/j.amjopharm.2007.10.003
发表时间：
2007-09-01
期刊：
The American journal of geriatric pharmacotherapy
影响因子：
--
作者：
Ramos-Bonner, Luz S;Goldberg, Todd H;Anastasopoulou, Catherine
通讯作者：
Anastasopoulou, Catherine
影响因子：
6.7
作者：
Iusuf, D.;van de Steeg, E.;Schinkel, A. H.
通讯作者：
Schinkel, A. H.