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Assessment of Protein Binding of 5‑Hydroxythalidomide Bioactivated in Humanized Mice with Human <i>P450 3A</i>-Chromosome or Hepatocytes by Two-Dimensional Electrophoresis/Accelerator Mass Spectrometry
Bioactivation
of 5-hydroxy-[<i>carbonyl</i>-<sup>14</sup>C]Âthalidomide,
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 <i>c</i> oxidase subunit
6B1 and ATP synthase subunit α in mice containing humanized <i>P450 3A</i> 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