In vivo formation of a glutathione conjugate derived from thalidomide in humanized uPA-NOG mice

Chem Res Toxicol. 2011 Mar 21;24(3):287-9. doi: 10.1021/tx200005g. Epub 2011 Feb 7.

Abstract

Metabolism of the teratogen thalidomide is proposed to be relevant to its toxicological action. We demonstrated the formation of the glutathione (GSH) conjugate of (R)-5-hydroxythalidomide in vivo in chimeric NOD-scid IL2Rg(null) mice with humanized livers (uPA-NOG mice). After an oral administration of racemic thalidomide (270 mg/kg), plasma concentrations of 5-hydroxythalidomide were significantly higher in humanized mice than in control mice. The GSH conjugate of 5-hydroxythalidomide was detected in the plasma. These results indicate that livers of humanized mice mediate thalidomide 5-hydroxylation and further oxidation leading to the GSH conjugate in vivo as well as in vitro and suggest that thalidomide activation occurs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aryl Hydrocarbon Hydroxylases / metabolism
  • Glutathione / analogs & derivatives*
  • Glutathione / chemistry
  • Glutathione / metabolism
  • Interleukin Receptor Common gamma Subunit / deficiency
  • Interleukin Receptor Common gamma Subunit / genetics*
  • Interleukin Receptor Common gamma Subunit / metabolism
  • Liver / metabolism
  • Mice
  • Mice, Transgenic
  • Microsomes, Liver / enzymology
  • Models, Animal
  • Oxidation-Reduction
  • Thalidomide / analogs & derivatives*
  • Thalidomide / chemistry
  • Thalidomide / metabolism
  • Urokinase-Type Plasminogen Activator / genetics*
  • Urokinase-Type Plasminogen Activator / metabolism

Substances

  • Interleukin Receptor Common gamma Subunit
  • Thalidomide
  • Aryl Hydrocarbon Hydroxylases
  • Urokinase-Type Plasminogen Activator
  • Glutathione