title: In vivo formation of a glutathione conjugate derived from thalidomide in humanized uPA-NOG mice.
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.
authors.affiliation: Showa Pharmaceutical University, Machida, Tokyo, Japan. hyamazak@ac.shoyaku.ac.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamazaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suemizu
authors.forename: Sho
authors.initials: S
authors.lastname: Igaya
authors.forename: Makiko
authors.initials: M
authors.lastname: Shimizu
authors.forename: Norio
authors.initials: N
authors.lastname: Shibata
authors.forename: Masato
authors.initials: M
authors.lastname: Nakamura
authors.forename: Goutam
authors.initials: G
authors.lastname: Chowdhury
authors.forename: F Peter
authors.initials: FP
authors.lastname: Guengerich
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D005978:Glutathione / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008862:Microsomes, Liver / Q000201:enzymology; D023421:Models, Animal; D010084:Oxidation-Reduction; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics* / Q000378:metabolism
chemical_list: D053631:Interleukin Receptor Common gamma Subunit; D013792:Thalidomide; D001189:Aryl Hydrocarbon Hydroxylases; D014568:Urokinase-Type Plasminogen Activator; D005978:Glutathione