CYP3A4, CYP2C9 and CYP2B6 expression and ifosfamide turnover in breast cancer tissue microsomes.
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Schmidt R, Baumann F, Knupfer H, Brauckhoff M, Horn LC, Schonfelder M, Kohler U, Preiss R
CYP3A4, CYP2C9 and CYP2B6 expression and ifosfamide turnover in breast cancer tissue microsomes.
Br J Cancer. 2004 Feb 23;90(4):911-6. doi: 10.1038/sj.bjc.6601492.
- PubMed ID
- 14970873 [ View in PubMed]
- Abstract
Ifosfamide is a prodrug that requires bioactivation by cytochrome P450 for antitumour activity. Up to now, little is known, to what extent in addition to the liver the ifosfamide metabolism may occur intratumorally. For this purpose, we investigated the expression of CYP3A4, CYP2C9 and CYP2B6 in breast cancer tissue using Western Blotting. Ifosfamide turnover was determined by detection of metabolites of the ifosfamide 4-hydroxylation and N-dechloroethylation in tumour microsomal incubations using HPLC/UV and LC/MS. The results demonstrate that all mammary tumours (n=11) reveal CYP3A4 expression; contents varied from 0.5 to 63 pmol mg(protein)(-1). CYP2C9 (n=9) was present in all tested breast tumour samples, too, while CYP2B6 (n=10) protein could not be detected. All measured breast cancer microsomes (n=4) showed an ifosfamide N-dechloroethylation capacity in the range from 0.04 to 0.21 pmol min(-1) mg(protein)(-1), while metabolites of the 4-hydroxylation could not be determined. In conclusion, the detected presence of CYP3A4 and CYP2C9 in breast tumours offers the possibility of intratumoral turnover of ifosfamide. For the first time in the literature, we could demonstrate a turnover of ifosfamide by microsomal preparations from human breast cancer tissue. A calculated modulation of intratumoral ifosfamide turnover could considerably influence its therapeutic efficiency.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Ifosfamide Cytochrome P450 2C9 Protein Humans UnknownSubstrateDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareIfosfamideThalidomide The metabolism of Ifosfamide can be increased when combined with Thalidomide. IfosfamideClozapine The metabolism of Ifosfamide can be increased when combined with Clozapine. IfosfamideChlorpromazine The metabolism of Ifosfamide can be increased when combined with Chlorpromazine. IfosfamideAmprenavir The metabolism of Ifosfamide can be increased when combined with Amprenavir. IfosfamideLorlatinib The metabolism of Ifosfamide can be increased when combined with Lorlatinib.