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

Yamazaki H, Suemizu H, Igaya S, Shimizu M, Shibata N, Nakamura M, Chowdhury G, Guengerich FP
Chem Res Toxicol. 2011 24 (3): 287-9

PMID: 21299192 · PMCID: PMC3838788 · DOI:10.1021/tx200005g

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.

MeSH Terms (12)

Animals Aryl Hydrocarbon Hydroxylases Glutathione Interleukin Receptor Common gamma Subunit Liver Mice Mice, Transgenic Microsomes, Liver Models, Animal Oxidation-Reduction Thalidomide Urokinase-Type Plasminogen Activator

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