...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Toxicology Letters: An International Journal Providing a Forum for Original and Pertinent Contributions in Toxicology Research >What is the contribution of human FMO3 in the N-oxygenation of selected therapeutic drugs and drugs of abuse?
【24h】

What is the contribution of human FMO3 in the N-oxygenation of selected therapeutic drugs and drugs of abuse?

机译：人体FMO3在选定治疗药物的N-氧合中的贡献是什么？

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Little is known about the role of flavin-containing monooxygenases (FMOs) in the metabolism of xenobiotics. FMO3 is the isoform in adult human liver with the highest impact on drug metabolism. The aim of the presented study was to elucidate the contribution of human FMO3 to the N-oxygenation of selected therapeutic drugs and drugs of abuse (DOAs). Its contribution to the in vivo hepatic net clearance of the N-oxygenation products was calculated by application of an extended relative activity factor (RAF) approach to differentiate from contribution of cytochrome P450 (CYP) isoforms. FMO3 and CYP substrates were identified using pooled human liver microsomes after heat inactivation and chemical inhibition, or single enzyme incubations. Kinetic parameters were subsequently determined using recombinant human enzymes and mass spectrometric analysis via authentic reference standards or simple peak areas of the products divided by those of the internal standard. FMO3 was identified as enzyme mainly responsible for the formation of N,N-diallyltryptamine N-oxide and methamphetamine hydroxylamine (>80% contribution for both). A contribution of 50 and 30% was calculated for the formation of N,N-dimethyltryptamine N-oxide and methoxypiperamide N-oxide, respectively. However, FMO3 contributed with less than 5% to the formation of 3-bromomethcathinone hydroxylamine, amitriptyline N-oxide, and clozapine N-oxide. There was no significant difference in the contributions when using calibrations with reference metabolite standards or peak area ratio calculations. The successful application of a modified RAF approach including FMO3 proved the importance of FMO3 in the N-oxygenation of DOAs in human metabolism. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
机译：关于含有黄素的单氧基酶（FMOS）在异恶蛋虫代谢中的作用很少。 FMO3是成人人肝中的同种型，对药物代谢的影响最高。本研究的目的是阐明人FMO3对所选治疗药物和滥用药物（DOAs）的N-氧合的贡献。通过施加延长的相对活动因子（RAF）方法来计算其对N-氧化产物的体内肝净净清除的贡献，以区分细胞色素P450（CYP）同种型的贡献。在热灭活和化学抑制之后使用合并的人肝微粒体鉴定FMO3和CYP底物，或者单一酶孵育。随后使用重组人酶和质谱分析通过正宗的参考标准或产品的简单峰面积来确定动力学参数，或者产品的简单峰面积除以内标。鉴定FMO3作为酶，主要负责形成N，N-二烯丙基N-氧化物和甲基苯丙胺羟胺（两者均为80％）。为了形成N，N-二甲基三丁胺N-氧化物和甲氧基哌酰胺N-氧化物，计算50和30％的贡献。然而，FMO3含量小于5％，形成3-溴甲腺嘌呤羟胺，氨基米N-氧化物和氯氮平N-氧化物的形成。使用校准用参考代谢物标准或峰面积比计算时，贡献没有显着差异。改进的RAF方法的成功应用包括FMO3证明了FMO3在人类新陈代谢中DOA的N-氧合中的重要性。 （c）2016 Elsevier Ireland Ltd.保留所有权利。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号