Showa Pharmaceutical University , Machida, Tokyo 194-8543, Japan.
Chem Res Toxicol. 2012 Feb 20;25(2):274-6. doi: 10.1021/tx300009j. Epub 2012 Jan 25.
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.
研究了 5-羟色胺酸二氢盐与谷胱甘肽（GSH）的缀合物在经过“人源化”肝脏修饰的嵌合小鼠中的形成：通过引入胸苷激酶，随后用更昔洛韦诱导，并移植人肝细胞，制备了新型人源化 TK-NOG 小鼠。经口给予外消旋沙利度胺（100mg/kg）后，人源化小鼠的血浆中 5-羟色胺酸和二氢沙利度胺的浓度高于对照组。给予 5-羟色胺酸（10mg/kg）后，检测到更高浓度的二氢沙利度胺。这些结果表明，人源化小鼠的肝脏介导沙利度胺氧化，导致儿茶酚和/或体内 GSH 缀合物，并表明沙利度胺发生了激活。
