The Effect of Repeated Administration of Cyclophosphamide on Cytochrome P450 2B in Rats

Abstract

Purpose: The prodrug cyclophosphamide (CPA) is activated by cytochrome P450 (CYP) enzymes. CPA is one of the corner stones in all cancer treatment. We have studied the effect of repeated doses of CPA given at different time intervals on the mRNA, protein levels, and enzyme activity of CYPs in rats. Experimental Design: Two groups of animals (A-75 and A-150) were treated with four doses of CPA (75 and 150 mg/kg, respectively) at short time intervals (6 h). The third group of animals (B-150) was treated with 150 mg/kg at 24-h intervals. Three animals were killed 30 min after administration, and three animals immediately before the next dose. Results: CYP2B1 and CYP2B2 mRNAs were significantly induced at 6 h after each dose in group A-75 (maximum of 2100-fold and 60-fold after the third dose, respectively), whereas the mRNA levels measured at 6 h postadministration in group A-150 were 1,490-fold and 36-fold after the second dose. In group B-150, no significant induction of mRNA levels was observed. CYP2B1 and CYP2B2 protein levels also increased with increased mRNAs. Plasma levels of 4-hydroxy-CPA measured at 30 min after dose correlated well with the increase in protein levels. Conclusion: Up-regulation of CYP2B mRNA, with a concomitant increase in protein expression and activity, were observed after repeated administration of low doses of CPA compared with that found using higher doses, possibly due to toxicity counteracting induction. These results may help in designing more effective dosing schedules for CPA.

Temporal Evaluation of CYP mRNA in Mice Administered with Prototypical P450 Inducers: Comparison with Conventional Protein/Enzyme Methods

“…A significant finding of this study was that maximal changes in gene expression, in most cases, were observed at the first time point evaluated (0.5 days), with the exception of CYP3a11 at Day 2 and CYP1a1 at Day 4. This transcriptional induction at an early time point has been observed in other studies (Goodsaid et al, 2003;Afsharian et al, 2007). The early maximal induction subsided to an elevated level, compared with the control.…”

“…Previously, we and others demonstrated the utility of transcriptional CYP analysis in rat studies (Goodsaid et al, 2003;Xie et al, 2005;Afsharian et al, 2007). Several studies reported good correlations in mouse with single or multiple time points (Martignoni et al, 2006;PustyInyak et al, 2007).…”

Synergistic Interactions between Christia vespertilionis Leaves Extract and Chemotherapy Drug Cyclophosphamide on WRL-68 Cell Line

“…WRL68 normal liver cell line was used to proceed with combination treatment of C. vespertilionis ethanolic extract and cyclophosphamide. This is because cyclophosphamide is extensively metabolized in the liver by cytochrome P450 enzymes via activation process 4hydroxylation producing active metabolite, 4hydroxycyclophosphamide that penetrates the cell membrane which then decomposes to phosphoramide mustard that alkylates DNA 25 . The combination index derived from the combination treatment tabulated in Table 2.…”

Moringa Oleifera Seed Extract Concomitantly Supplemented with Chemotherapy Worsens Tumor Progression in Mice with Triple Negative Breast Cancer and Obesity

“…The transcription of CYP2J2 , known to metabolize cyclophosphamide [ 64 ], was upregulated in the tumors by chemotherapy alone and by combination therapy. This upregulation of CYP2J2 is not surprising as exposure to cyclophosphamide can increase the transcription and expression of cyclophosphamide metabolizing enzymes [ 69 ]. Ultimately, more research is needed to truly understand the complex mechanisms involved in herb–drug interactions and their impact on clinical outcomes.…”