Nuclear receptor mediated induction of cytochrome P450 3A4 by anticancer drugs: a key role for the pregnane X receptor.
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Harmsen S, Meijerman I, Beijnen JH, Schellens JH
Nuclear receptor mediated induction of cytochrome P450 3A4 by anticancer drugs: a key role for the pregnane X receptor.
Cancer Chemother Pharmacol. 2009 Jun;64(1):35-43. doi: 10.1007/s00280-008-0842-3. Epub 2008 Oct 7.
- PubMed ID
- 18839173 [ View in PubMed]
- Abstract
PURPOSE: Induction of cytochrome P450 (CYP) 3A4, an enzyme that is involved in the biotransformation of more than 50% of all drugs, by xenobiotics is an important cause of pharmacokinetic drug-drug interactions in oncology. In addition to rifampicin and hyperforin, the anticancer drug paclitaxel has also been shown to be an inducer of CYP3A4 via activation of the pregnane X receptor (PXR). We therefore screened 18 widely used anticancer drugs for their ability to activate PXR-mediated CYP3A4 induction. METHODS: A CYP3A4 reporter gene assay was employed to identify PXR agonists among the eighteen anticancer drugs. Subsequently CYP3A4 mRNA and protein expression following treatment with these PXR agonists was assessed. Finally, the effect of pre-treatment with these agents on the 1'-hydroxylation of midazolam (a specific CYP3A4 probe) was determined. RESULTS: Paclitaxel, erlotinib, tamoxifen, ifosfamide, flutamide and docetaxel are able to activate PXR, while only strong PXR activation leads to significant induction of CYP3A4 activity. CONCLUSIONS: The identified PXR agonists may have the propensity to cause clinically relevant drug-drug interactions as a result of CYP3A4 induction.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Cyclophosphamide Nuclear receptor subfamily 1 group I member 2 Protein Humans UnknownNot Available Details Erlotinib Nuclear receptor subfamily 1 group I member 2 Protein Humans YesAgonistDetails Flutamide Nuclear receptor subfamily 1 group I member 2 Protein Humans UnknownNot Available Details Ifosfamide Nuclear receptor subfamily 1 group I member 2 Protein Humans UnknownNot Available Details Paclitaxel Nuclear receptor subfamily 1 group I member 2 Protein Humans UnknownInducerDetails Tamoxifen Nuclear receptor subfamily 1 group I member 2 Protein Humans UnknownNot Available Details - Pharmaco-transcriptomics
Drug Drug Groups Gene Gene ID Change Interaction Chromosome Cyclophosphamide Approved Investigational CYP3A4 1576 upregulated Cyclophosphamide results in increased expression of CYP3A4 mRNA 7q22.1 Docetaxel Approved Investigational CYP3A4 1576 upregulated docetaxel results in increased expression of CYP3A4 mRNA 7q22.1 Erlotinib Approved Investigational CYP3A4 1576 upregulated Erlotinib Hydrochloride results in increased expression of CYP3A4 mRNA 7q22.1 Flutamide Approved Investigational CYP3A4 1576 upregulated Flutamide results in increased expression of CYP3A4 mRNA 7q22.1 Ifosfamide Approved CYP3A4 1576 upregulated Ifosfamide results in increased expression of CYP3A4 mRNA 7q22.1 Paclitaxel Approved Vet Approved CYP3A4 1576 upregulated Paclitaxel results in increased expression of CYP3A4 mRNA 7q22.1 Rifampicin Approved CYP3A4 1576 upregulated Rifampin results in increased expression of CYP3A4 mRNA 7q22.1 Tamoxifen Approved CYP3A4 1576 upregulated Tamoxifen results in increased expression of CYP3A4 mRNA 7q22.1 - Pharmaco-proteomics
Drug Drug Groups Gene Gene ID Change Interaction Chromosome Rifampicin Approved CYP3A4 1576 increased Rifampin results in increased expression of CYP3A4 protein 7q22.1 Rifampicin Approved CYP3A4 1576 increased Rifampin results in increased expression of CYP3A4 protein 7q22.1 Rifampicin Approved CYP3A4 1576 increased Rifampin results in increased expression of CYP3A4 protein 7q22.1