Murine strain differences in metabolism and bladder toxicity of cyclophosphamide

Cyclophosphamide (CP) undergoes metabolic activation, generating phosphoramide mustard and acrolein which are believed to be responsible for the cytostatic and toxic effects, respectively. In this study, CP-induced bladder toxicity (hemorrhagic cystitis) was found to be significantly greater in the ICR than the C57BL/6N (C-57) strain of mice. Strain differences exist in the distribution of CP metabolites to the bladder, as evidenced by consistently higher levels of acrolein equivalents measured in the urine of the sensitive ICR strain. These differences may arise from strain variation in the oxidative metabolism of CP by the mixed-function oxidase system. However, intrinsic factors within the bladder may also be involved in the resistance exhibited by C-57 mice. Support for this hypothesis is provided by the significant increase in hemorrhagic response and permeability of ICR compared to C-57 bladders exposed to equivalent levels of acrolein by intravesicle instillation. Basal protein thiol levels were higher in C-57 than in the ICR strain. However, the effects of acrolein on protein thiol content did not correlate with toxicity suggesting that these groups are not the critical targets for CP-induced bladder injury.