IN-VIVO AND IN-VITRO EVALUATIONS FOR THE EFFECT OF CYCLOPHOSPHAMIDE ON THE CARCINOGEN METABOLIZING SYSTEM OF MOUSE-LIVER MICROSOMES

The effect of the antineoplastic immunosuppressive alkylating agent cyclophosphamide (CPhA) on the modification of the carcinogen-metabolizing capacity was studied in vivo in mouse liver microsomes at different durations of treatment, from one to six consecutive days. The in vitro effect of increasing concentrations of the drug upon this enzyme system was also investigated. Following the administration of CPhA, a significant time-dependent decrease was observed in the activity of the low substrate level of the hepatic microsomal N-nitrosodimethylamine demethylase (NDMAdII). The high substrate level of the enzyme (NDMAdII) also exhibited a similar decrease which was not a subject for the treatment intervals where the greatest decrease (-60%; p<0.05) emerged at day 3 of the administration-point. The activity of the aryl hydrocarbon (benzo(alpha)pyrene) hydroxylase (AHH) revealed a significant increase at the single dose of CPhA, while at the repeated dose treatment (for 3 days) no alteration was noticed in the enzyme activity. This figure of expression in AHH was reversed to a significant inhibition at the 6 day-repeated dose, the time-point at which an almost identical effect was also observed in the hepatic content of cytochrome P450. The alterations in the metabolism of NDMA and benzo(alpha)pyrene which had been seen in the in vivo assays was further confirmed by the results of the in vitro experiment.