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

作者：Yamazaki Hiroshi^*; Suemizu Hiroshi; Kazuki Yasuhiro; Oofusa Ken; Kuribayashi Shunji; Shimizu Makiko; Ninomiya Shinichi; Horie Toru; Shibata Norio; Guengerich F Peter

来源：Chemical Research in Toxicology, 2016, 29(8): 1279-1281.

DOI：10.1021/acs.chemrestox.6b00210

Bioactivation of 5-hydroxy-[carbonyl-C-14]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 a 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.

• 出版日期2016-8