Metabolism-Dependent Toxicities of Cyclophosphamide and Protection by N-Acetylcysteine and Other Thiols

Our investigations spanning over the past six years have implicated cyclophosphamide (CP) metabolite acrolein in some specific biochemical and systemic toxicities of CP. Acrolein is implicated in the depletion of hepatic glutathione, in the depression of hepatic microsomal mixed function oxidase system (MFO), and in the induction of urotoxicity either per se or in conjunction with other CP metabolites. Acrolein-associated toxicities appear to arise as a consequence of the formation of covalent adducts between acrolein and critical sulfhydryl groups in protein-bound thiols. These specific toxicities of CP are blocked by exogenous thiols such as N-acetylcysteine (NAC) and mesnum (2-mercaptoethanesulfonate). However, combination of CP with the exogenous thiols does not interfere with the immunosuppressive (i.e. myelosuppressive) and carcinostatic properties of CP, which appear to be the consequence of metabolism-dependent formation of the alkylating metabolites of CP, presumably phosphoramide mustard.