title: 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.
abstract: 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.
authors.affiliation: School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia.
authors.forename: M T
authors.initials: MT
authors.lastname: Angley
authors.forename: L N
authors.initials: LN
authors.lastname: Sansom
authors.forename: I
authors.initials: I
authors.lastname: Stupans
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000494:pharmacology*; D001711:Biotransformation / Q000187:drug effects; D015153:Blotting, Western; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004958:Estradiol / Q000097:blood; D005260:Female; D007527:Isoenzymes / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008168:Lung / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012727:Sex Characteristics; D013739:Testosterone / Q000097:blood; D013963:Thyroid Hormones / Q000097:blood
chemical_list: D018906:Antineoplastic Agents, Alkylating; D007527:Isoenzymes; D013963:Thyroid Hormones; D013739:Testosterone; D004958:Estradiol; D003520:Cyclophosphamide; D003577:Cytochrome P-450 Enzyme System; D009251:NADPH-Ferrihemoprotein Reductase