In vivo studies on the transformation of cyclophosphamide to mutagenic metabolites

: Cyclophosphamide (CP), a widely used antineoplastic drug, requires hepatic mixed-function-oxidase-mediated activation to show alkylating activity as well as cytotoxicity, oncogenic transformation and chromosomal aberrations. Evidences are here reported that in vivo activation of CP to urinary mutagenic metabolites is catalyzed primarily by a phenobarbital-inducible cytochrome P-450 system. 24 hours urines from male Sprague-Dawley rats treated i.p. by a single CP administration were filtered through XAD-2 columns and mutagenicity of the acetonic extract was assayed by the Ames test in absence of enzymatic microsomal activation. a highly positive response with a linear dose-dependence was obtained in the range 0.500 mg/kg of CP. Treating rats with Phenobarbital, before CP (500 mg/kg) administration, induced a 250% increase in urine mutagenic activity, whereas. -Naphthoflavone pretreatment reduced the CP activation to urine mutagenic metabolites to 51% as compared with control CP-treated rats.