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.

Yamazaki H, Suemizu H, Kazuki Y, Oofusa K, Kuribayashi S, Shimizu M, Ninomiya S, Horie T, Shibata N, Guengerich FP
Chem Res Toxicol. 2016 29 (8): 1279-81

PMID: 27464947 · PMCID: PMC5282975 · DOI:10.1021/acs.chemrestox.6b00210

Bioactivation of 5-hydroxy-[carbonyl-(14)C]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.

MeSH Terms (9)

Animals Cytochrome P-450 Enzyme System Electrophoresis, Gel, Two-Dimensional Hepatocytes Humans Mass Spectrometry Mice Protein Binding Thalidomide

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