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 cy clophosphamide (CPhA) on the modification of the carcinogen-metabolizi ng capacity was studied in vivo in mouse liver microsomes at different durations of treatment, from one to six consecutive days. The in vitr o effect of increasing concentrations of the drug upon this enzyme sys tem was also investigated. Following the administration of CPhA, a sig nificant time-dependent decrease was observed in the activity of the l ow substrate level of the hepatic microsomal N-nitrosodimethylamine de methylase (NDMAdII). The high substrate level of the enzyme (NDMAdII) also exhibited a similar decrease which was not a subject for the trea tment intervals where the greatest decrease (-60%; p<0.05) emerged at day 3 of the administration-point. The activity of the aryl hydrocarbo n (benzo(alpha)pyrene) hydroxylase (AHH) revealed a significant increa se at the single dose of CPhA, while at the repeated dose treatment (f or 3 days) no alteration was noticed in the enzyme activity. This figu re of expression in AHH was reversed to a significant inhibition at th e 6 day-repeated dose, the time-point at which an almost identical eff ect was also observed in the hepatic content of cytochrome P450. The a lterations in the metabolism of NDMA and benzo(alpha)pyrene which had been seen in the in vivo assays was further confirmed by the results o f the in vitro experiment.