Cyclophosphamide administered repeatedly to the male rat and as a single dose to the female rat. Its effects on hepatic and pulmonary P450 and associated enzymes

Xenobiotica. 1995 Nov;25(10):1051-62. doi: 10.3109/00498259509061905.


1. Two different aspects of the effects of the cytotoxic agent cyclophosphamide (CP) on rat P450 and associated enzymes have been examined. 2. First, the effects of CP, administered as a single 200 mg/kg dose, on hepatic and pulmonary P450 and some associated enzymes in the female rat have been investigated. Second, the effects of repeat doses of CP (40 mg/kg on days 0-4 with killing on days 5, 8 and 11) to the male rat have been examined. 3. CP decreased the activity of the female rat hepatic enzymes 2A1, 2C6 and/or 2C12 and 2E1, NADPH-P450 oxidoreductase and 17 beta-oxidoreductase and the pulmonary enzyme 2B, 7 days after its administration. The decreases in the activity of the enzymes 2E1 and NADPH-P450 oxidoreductase were accompanied by a corresponding change in the amount of enzyme protein indicating that the alteration in expression of these enzymes occurred via changes in transcription and/or translation or protein degradation. 4. CP also impaired its own activation 7 days after its administration to the female rat. 5. The change in female enzyme profile was accompanied by a reduction in the hormones oestradiol, T4 and T3 7 days after CP administration. 6. Despite an apparent trend for an increase in activity on day 5, a decrease on day 8 and a subsequent increase on day 11, repeat doses of CP to the male rat generally did not alter the P450 isoforms 2A2, 2B1, 2C11, 2E1 and 3A2 or 17 beta-oxidoreductase, NADPH-P450 oxidoreductase and steroid 5 alpha-reductase. 7. Chronic administration of CP to the male rat significantly reduced erythromycin demethylase and NADPH-P450 oxidoreductase 8 days following commencement of dosing and significantly increased 2A2 11 days following commencement of dosing. There was also a statistically significant increase in pulmonary 2B 5 days following commencement of dosing. 8. Plasma testosterone and TSH were unchanged following repeated dosing with CP while T3 was significantly decreased on days 5, 8 and 11 and T4 was significantly decreased on day 8.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Alkylating / administration & dosage
  • Antineoplastic Agents, Alkylating / pharmacology*
  • Biotransformation / drug effects
  • Blotting, Western
  • Cyclophosphamide / administration & dosage
  • Cyclophosphamide / pharmacology*
  • Cytochrome P-450 Enzyme System / metabolism*
  • Estradiol / blood
  • Female
  • Isoenzymes / metabolism*
  • Liver / drug effects
  • Liver / enzymology*
  • Lung / drug effects
  • Lung / enzymology*
  • Male
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology
  • NADPH-Ferrihemoprotein Reductase / metabolism
  • Rats
  • Rats, Wistar
  • Sex Characteristics
  • Testosterone / blood
  • Thyroid Hormones / blood


  • Antineoplastic Agents, Alkylating
  • Isoenzymes
  • Thyroid Hormones
  • Testosterone
  • Estradiol
  • Cyclophosphamide
  • Cytochrome P-450 Enzyme System
  • NADPH-Ferrihemoprotein Reductase