In vivo formation of dihydroxylated and glutathione conjugate metabolites derived from thalidomide and 5-Hydroxythalidomide in humanized TK-NOG mice

Chem Res Toxicol. 2012 Feb 20;25(2):274-6. doi: 10.1021/tx300009j. Epub 2012 Jan 25.


The formation of dihydroxythalidomide and glutathione (GSH) conjugate(s) of 5-hydroxythalidomide was investigated in chimeric mice modified with "humanized" liver: novel humanized TK-NOG mice were prepared by the introduction of thymidine kinase, followed by induction with ganciclovir, and human liver cells were transplanted. Following oral administration of racemic thalidomide (100 mg/kg), plasma concentrations of 5-hydroxy- and dihydroxythalidomide were higher in humanized mice than in controls. After administration of 5-hydroxythalidomide (10 mg/kg), higher concentrations of dihydroxythalidomide were detected. These results indicate that livers of humanized mice mediate thalidomide oxidation, leading to catechol and/or the GSH conjugate in vivo and suggest that thalidomide activation occurs.

MeSH terms

  • Animals
  • Chimera
  • Glutathione / metabolism
  • Hepatocytes / metabolism
  • Humans
  • Hydroxylation
  • Mice
  • Teratogens / pharmacokinetics*
  • Thalidomide / analogs & derivatives*
  • Thalidomide / blood
  • Thalidomide / metabolism
  • Thalidomide / pharmacokinetics*


  • 5'-hydroxythalidomide
  • Teratogens
  • 5-hydroxythalidomide
  • Thalidomide
  • Glutathione