Identification of a reactive glutathione conjugate as a metabolite of SR-2508 in CHO cells.
Reaction between GSH and the hydroxylamine derivative of SR-2508 results in the formation of two stable conjugates identified as 2-amino-4-S-glutathionyl and 2-amino-5-S-glutathionyl imidazoles. These stable conjugates are apparently formed from a reactive derivative of the hydroxylamine that is sufficiently stable to be isolated after HPLC separation. The physical and chemical properties of this derivative are consistent with it being a GSH conjugate in which the glutathionyl residue is attached to the 2-amino nitrogen of the imidazole moiety through sulphur. With excess GSH, under physiological conditions, it forms a mixture of the two stable GSH conjugates. In CHO cells exposed to SR-2508 under hypoxic conditions, this unstable GSH conjugate has been detected and suggests the possibility of GSH functioning as a carrier of a toxic metabolite of 2-nitroimidazoles under certain conditions.
D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D017341:Etanidazole; D005978:Glutathione / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism*; D007093:Imidazoles / Q000032:analysis*; D066298:In Vitro Techniques; D009593:Nitroimidazoles / Q000378:metabolism*; D011838:Radiation-Sensitizing Agents / Q000378:metabolism*
D007093:Imidazoles; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; C049946:1-N-(2-hydroxyethyl)acetamido-2-hydroxylaminoimidazole-glutathione conjugate; D017341:Etanidazole; D005978:Glutathione