Investigation of the mechanism by which cyclophosphamide alters cytochrome P450 in male rats.
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.
McClure
M T
MT
School of Pharmacy, University of South Australia, Adelaide.
Stupans
I
I
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
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