Effects of 5-fluorouracil treatment on rat liver microsomal enzymes.
1. The effects of the administration of the anticancer drug 5-fluorouracil on P450-mediated metabolizing capacity, and the activity of several related enzymes were examined by comparing two different dosage regimes, 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-fluorouracil (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 microsomes were assayed for total P450 content, reduced nicotinamide adenine dinucleotide phosphate-P450-reductase, aminopyrine demethylase, cyclophosphamide 4-hydroxylase, aniline hydroxylase, androstenedione 6 beta- and 16 alpha-hydroxylase and delta 4-3-oxo-steroid 5 alpha-oxidoreductase activity. 3. The animals that received 5-fluorouracil as a single, high dose did not show any alterations in any of the measured parameters at any of the times at which they were killed. 4. The animals that received chronic low doses of 5-fluorouracil, however, showed a statistically significant decrease in androstenedione 6 beta- and 16 alpha-hydroxylase and cyclophosphamide 4-hydroxylase activity and a statistically significant increase in delta 4-3-oxo-steroid 5 alpha-oxidoreductase activity 4 and 7 days after completion of dosing. 5. Immunoquantified P4502C11 and 3A content was also decreased at these time points. These alterations occurred concurrently with depleted plasma testosterone levels in the groups that received repeated low doses of 5-fluorouracil.
Stupans
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School of Pharmacy and Medical Science, University of South Australia, Adelaide.
Richards
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DA
McClure
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MT
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism; D000633:Aminopyrine N-Demethylase / Q000378:metabolism; D000815:Aniline Hydroxylase / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005472:Fluorouracil / Q000008:administration & dosage* / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009251:NADPH-Ferrihemoprotein Reductase; D010088:Oxidoreductases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000378:metabolism; D013739:Testosterone / Q000032:analysis* / Q000097:blood
D013739:Testosterone; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D013250:Steroid Hydroxylases; D000815:Aniline Hydroxylase; D039181:Steroid 16-alpha-Hydroxylase; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; D000633:Aminopyrine N-Demethylase; D009251:NADPH-Ferrihemoprotein Reductase; D005472:Fluorouracil