Effects in vivo of lymphoma ascites tumors and procarbazine, alone and in combination, upon hepatic drugmetabolizing enzymes of mice

Abstract

Studies have been conducted on hepatic microsomal enzymes after treatment of two strains of male mice, BDF 1 and DBA/2J, each with a single dose (300 mg/kg body weight) of procarbazine (PCZ) hydrochloride alone or in combination with a 6- to 7-day prior implantation of murine leukemic lymphoma L5178Y ascites cells. Mice were sacrificed at 4, 8 or 16 hr after i.p. injection of PCZ and found to possess levels of microsomal aniline hydroxylase, ethylmorphine N-demethylase, nitrobenzoate reductase activities and cytochrome P-450 content which were depressed to 78, 76, 54 and 61 per cent of untreated controls, respectively, for BDF 1 mice and 61, 51, 39 and 51 per cent of untreated controls, respectively, for DBA/2J mice. Mice implanted with lymphoma cells and sacrificed 6–7 days later without PCZ treatment had hepatic microsomal enzyme activity levels which were depressed to about the same extent as those receiving PCZ treatment only. PCZ treatment 6–7 days after lymphoma implantation caused severe depression of microsomal enzyme activities in both mouse strains. The maximum depressions expressed as per cent of untreated controls were: cytochrome P-450, 33 per cent; aniline hydroxylase, 32 per cent; ethylmorphine N-demethylase, 33 per cent; and nitrobenzoate reductase, 33 per cent. As a possible explanation for the PCZ effects, it is proposed that PCZ is serving as a tightly bound competitive substrate to cytochrome P-450-related enzyme systems.