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In Vivo Formation of Dihydroxylated and Glutathione Conjugate Metabolites Derived from Thalidomide and 5-Hydroxythalidomide in Humanized TK-NOG Mice

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Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan,
Central Institute for Experimental Animals, Kawasaki-ku, Kawasaki 210-0821, Japan
§ Graduate School of Engineering, Nagoya Institute of Technology, Showa-ku, Nagoya 466-8555, Japan
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States
*(H.Y.) Showa Pharmaceutical University, 3-3165 Higashi-tamagawa Gakuen, Machida, Tokyo 194-8543, Japan. Tel: +81-42-721-1406. Fax: +81-42-721-1406. E-mail: [email protected]. (F.P.G.) Tel: (615) 322-2261. Fax: (615) 322-4349. E-mail: [email protected]
Cite this: Chem. Res. Toxicol. 2012, 25, 2, 274–276
Publication Date (Web):January 23, 2012
https://doi.org/10.1021/tx300009j
Copyright © 2012 American Chemical Society

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    Abstract

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    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.

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    Experimental procedures, a representative ESI-LC-MS/MS chromatogram of the dihydroxythalidomide in vitro, and a representative ESI-LC-MS/MS chromatogram of dihydroxythalidomide formed in vivo. This material is available free of charge via the Internet at http://pubs.acs.org.

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