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 200mg/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 (40mg/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 17β-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 17β-oxidoreductase, NADPH-P450 oxidoreductase and steroid 5α-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.