Investigation of the mechanism by which cyclophosphamide alters cytochrome P450 in male rats

Biochem Pharmacol. 1992 Jun 23;43(12):2655-8. doi: 10.1016/0006-2952(92)90155-c.

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.

MeSH terms

  • Acetylcysteine / administration & dosage
  • Acetylcysteine / pharmacology
  • Aminopyrine N-Demethylase / analysis
  • Animals
  • Aryl Hydrocarbon Hydroxylases*
  • Biotransformation
  • Cyclophosphamide / administration & dosage
  • Cyclophosphamide / pharmacokinetics
  • Cyclophosphamide / pharmacology*
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / analysis
  • Cytochrome P-450 Enzyme System / metabolism*
  • Half-Life
  • In Vitro Techniques
  • Male
  • Microsomes, Liver / drug effects*
  • Microsomes, Liver / enzymology
  • NADPH-Ferrihemoprotein Reductase / analysis
  • Oxidoreductases, N-Demethylating / analysis
  • Rats
  • Rats, Inbred Strains
  • Steroid Hydroxylases / analysis

Substances

  • Cytochrome P-450 Enzyme Inhibitors
  • Cyclophosphamide
  • Cytochrome P-450 Enzyme System
  • Steroid Hydroxylases
  • Aryl Hydrocarbon Hydroxylases
  • Cytochrome P-450 CYP3A
  • Oxidoreductases, N-Demethylating
  • Aminopyrine N-Demethylase
  • NADPH-Ferrihemoprotein Reductase
  • Acetylcysteine