title: Investigation of the mechanism by which cyclophosphamide alters cytochrome P450 in male rats.
abstract: The effects of administration of the cytotoxic agent cyclophosphamide on cytochrome P450 have been examined in the liver microsomes of male rats. Microsomes were prepared after cyclophosphamide administration 1, 4 or 7 days prior to killing. The coadministration of cyclophosphamide with N-acetylcysteine has also been investigated. The microsomes were assayed for NADPH cytochrome P450 reductase, aminopyrine demethylase, erythromycin demethylase and androstenedione hydroxylase activities. Activities were generally unchanged 1 and 4 days after cyclophosphamide administration and were significantly decreased at 7 days. N-Acetylcysteine did not alter the effects of cyclophosphamide at 7 days. The effect of cyclophosphamide in vitro has also been examined. Microsomes from untreated animals were subjected to the above assays following in vitro metabolic activation of cyclophosphamide in a reconstituted system in the presence and absence of N-acetylcysteine. All enzyme activities were significantly reduced by the cyclophosphamide metabolites. The presence of N-acetylcysteine prevented this inactivation. The results of these investigations suggest that cyclophosphamide inactivates hepatic cytochrome P450 in vitro and in vivo via different mechanisms.
authors.affiliation: School of Pharmacy, University of South Australia, Adelaide.
authors.forename: M T
authors.initials: MT
authors.lastname: McClure
authors.forename: I
authors.initials: I
authors.lastname: Stupans
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage / Q000494:pharmacology; D000633:Aminopyrine N-Demethylase / Q000032:analysis; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001711:Biotransformation; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000378:metabolism*; D006207:Half-Life; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D009251:NADPH-Ferrihemoprotein Reductase / Q000032:analysis; D010089:Oxidoreductases, N-Demethylating / Q000032:analysis; D051381:Rats; D011919:Rats, Inbred Strains; D013250:Steroid Hydroxylases / Q000032:analysis
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D003520:Cyclophosphamide; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D000633:Aminopyrine N-Demethylase; D009251:NADPH-Ferrihemoprotein Reductase; D000111:Acetylcysteine