Assessment of Protein Binding of 5-Hydroxythalidomide Bioactivated in Humanized Mice with Human P450 3A-Chromosome or Hepatocytes by Two-Dimensional Electrophoresis/Accelerator Mass Spectrometry

详细信息    查看全文

• 作者：Hiroshi Yamazaki ; Hiroshi Suemizu ; Yasuhiro Kazuki ; Ken Oofusa ; Shunji Kuribayashi ; Makiko Shimizu ; Shinichi Ninomiya ; Toru Horie ; Norio Shibata ; F. Peter Guengerich
• 刊名：Chemical Research in Toxicology
• 出版年：2016
• 出版时间：August 15, 2016
• 年：2016
• 卷：29
• 期：8
• 页码：1279-1281
• 全文大小：196K
• 年卷期：0
• ISSN：1520-5010

文摘

Bioactivation of 5-hydroxy-[carbonyl-¹⁴C]thalidomide, a known metabolite of thalidomide, by human artificial or native cytochrome P450 3A enzymes, and nonspecific binding in livers of mice was assessed using two-dimensional electrophoresis combined with accelerator mass spectrometry. The apparent major target proteins were liver microsomal cytochrome c oxidase subunit 6B1 and ATP synthase subunit α in mice containing humanized P450 3A genes or transplanted humanized liver. Liver cytosolic retinal dehydrogenase 1 and glutathione transferase A1 were targets in humanized mice with P450 3A and hepatocytes, respectively. 5-Hydroxythalidomide is bioactivated by human P450 3A enzymes and trapped with proteins nonspecifically in humanized mice.