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

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• 作者：Hiroshi Yamazaki ; Hiroshi Suemizu ; Makiko Shimizu ; Sho Igaya ; Norio Shibata ; Masato Nakamura ; Goutam Chowdhury ; F. Peter Guengerich
• 刊名：Chemical Research in Toxicology
• 出版年：2012
• 出版时间：February 20, 2012
• 年：2012
• 卷：25
• 期：2
• 页码：274-276
• 全文大小：191K
• 年卷期：v.25,no.2(February 20, 2012)
• ISSN：1520-5010

文摘

The formation of dihydroxythalidomide and glutathione (GSH) conjugate(s) of 5-hydroxythalidomide was investigated in chimeric mice modified with 鈥渉umanized鈥?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.