Showa Pharmaceutical University, Machida, Tokyo, Japan.
Chem Res Toxicol. 2011 Mar 21;24(3):287-9. doi: 10.1021/tx200005g. Epub 2011 Feb 7.
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.
致畸剂沙利度胺的代谢被认为与其毒理学作用有关。我们在具有人源化肝脏的嵌合 NOD-scid IL2Rg(null) 小鼠（uPA-NOG 小鼠）中体内证明了（R）-5-羟基沙利度胺与谷胱甘肽（GSH）的缀合物的形成。在口服给予外消旋沙利度胺（270mg/kg）后，人源化小鼠的血浆 5-羟基沙利度胺浓度明显高于对照小鼠。在血浆中检测到 5-羟基沙利度胺的 GSH 缀合物。这些结果表明，人源化小鼠的肝脏介导沙利度胺 5-羟化作用和进一步氧化，导致体内以及体外形成 GSH 缀合物，并提示沙利度胺发生激活。
