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

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

Author information

1
Showa Pharmaceutical University, Machida, Tokyo, Japan. hyamazak@ac.shoyaku.ac.jp

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.

PMID:
21299192
PMCID:
PMC3838788
DOI:
10.1021/tx200005g
[Indexed for MEDLINE]
Free PMC Article

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