EFFECTS OF 5-FLUOROURACIL TREATMENT ON RAT-LIVER MICROSOMAL-ENZYMES

1. The effects of the administration of the anticancer drug 5-fluorour acil on P450-mediated metabolizing capacity, and the activity of sever al related enzymes were examined by comparing two different dosage reg imes, i.e. a single ip dose of 5-fluorouracil (120 mg/kg) at 1, 4 and 7 days prior to killing, and a repeated dose regimen of 5-flourouracil (24 mg/kg/day for 5 consecutive days) with animals being killed at 1, 4 and 7 days after the last 5-fluorouracil dose. 2. Rat liver microso mes were assayed for total P450 content, reduced nicotinamide adenine dinucleotide phosphate-P450-reductase, aminopyrine demethylase, cyclop hosphamide 4-hydroxylase, aniline hydroxylase, androstenedione 6 beta- and 16 alpha-hydroxylase and Delta(4)-3-oxo-steroid 5 alpha-oxidoredu ctase activity. 3. The animals that received 5-fluorouracil as a singl e, high dose did not show any alterations in any of the measured param eters at any of the times at which they were killed. 4. The animals th at received chronic low doses of 5-fluorouracil, however, showed a sta tistically significant decrease in androstenedione 6 beta- and 16 alph a-hydroxylase and cyclophosphamide 4-hydroxylase activity and a statis tically significant increase in Delta(4)-3-oxo-steroid 5 alpha-oxidore ductase activity 4 and 7 days after completion of dosing. 5. Immunoqua ntified P4502C11 and 3A content was also decreased at these time point s. These alterations occurred concurrently with depleted plasma testos terone levels in the groups that received repeated low doses of 5-fluo rouracil.