Effects of 5-fluorouracil on drug-metabolizing enzymes in the rat.

The effect of pretreatment of rats with 5-fluorouracil (5-FU) on hepatic drug-metabolizing enzyme activities was examined. Male rats, weighing 165g, were given a single i.p. injection of 5-FU, 120 mg/kg, and 7 days later the drug-metabolizing enzyme activities of a 10,000 x g supernatant fraction from liver homogenates were exam ined. Aniline hydroxylase, ethylmorphine /V-demethylase, and 2-(methylthio)benzothiazole S-demethylase activities were depressed 41, 40, and 25%, respectively, while the protein content of the 10,000 x g supernatant fraction was unchanged. On Day 7, pentobarbital sleeping time was increased 80% compared to controls. On Day 7, control and 5-FU-treated rats weighed 212 and 165g, respectively, while on Day 14 when they weighed 249 and 195 g, respectively, there no longer were differences in enzyme activities. Seven days after two successive daily i.p. injections of 5-FU, 60 mg/kg, aniline hydroxylase and ethylmorphine /V-demethylase activities were depressed while S-(methylthio)benzothiazole .S-demethylase was unchanged. Activation in vitro of cyclophosphamide to alkylating metabolites by 10,000 x g supernatant fraction of liver homogenates from rats 7 days after pretreatment with 5-FU, 120 mg/kg, was de creased 25% compared to controls. Decreases occurred in body and liver weights 7 and 14 days after 5-FU pretreat ment. However, there was no apparent correlation between these decreases and the changes in enzyme activities. The depression of hepatic drug-metabolizing enzyme activities after pretreatment with 5-FU may be due to the direct action of the drug on^the synthesis and/or turnover of these