Nuclear receptor mediated induction of cytochrome P450 3A4 by anticancer drugs: a key role for the pregnane X receptor.

Article Details

Citation

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
DrugTargetKindOrganismPharmacological ActionActions
CyclophosphamideNuclear receptor subfamily 1 group I member 2ProteinHumans
Unknown
Not AvailableDetails
ErlotinibNuclear receptor subfamily 1 group I member 2ProteinHumans
Yes
Agonist
Details
FlutamideNuclear receptor subfamily 1 group I member 2ProteinHumans
Unknown
Not AvailableDetails
IfosfamideNuclear receptor subfamily 1 group I member 2ProteinHumans
Unknown
Not AvailableDetails
PaclitaxelNuclear receptor subfamily 1 group I member 2ProteinHumans
Unknown
Inducer
Details
TamoxifenNuclear receptor subfamily 1 group I member 2ProteinHumans
Unknown
Not AvailableDetails
Pharmaco-transcriptomics
DrugDrug GroupsGeneGene IDChangeInteractionChromosome
CyclophosphamideApproved InvestigationalCYP3A41576
upregulated
Cyclophosphamide results in increased expression of CYP3A4 mRNA7q22.1
DocetaxelApproved InvestigationalCYP3A41576
upregulated
docetaxel results in increased expression of CYP3A4 mRNA7q22.1
ErlotinibApproved InvestigationalCYP3A41576
upregulated
Erlotinib Hydrochloride results in increased expression of CYP3A4 mRNA7q22.1
FlutamideApproved InvestigationalCYP3A41576
upregulated
Flutamide results in increased expression of CYP3A4 mRNA7q22.1
IfosfamideApprovedCYP3A41576
upregulated
Ifosfamide results in increased expression of CYP3A4 mRNA7q22.1
PaclitaxelApproved Vet ApprovedCYP3A41576
upregulated
Paclitaxel results in increased expression of CYP3A4 mRNA7q22.1
RifampinApprovedCYP3A41576
upregulated
Rifampin results in increased expression of CYP3A4 mRNA7q22.1
TamoxifenApprovedCYP3A41576
upregulated
Tamoxifen results in increased expression of CYP3A4 mRNA7q22.1
Pharmaco-proteomics
DrugDrug GroupsGeneGene IDChangeInteractionChromosome
RifampinApprovedCYP3A41576
increased
Rifampin results in increased expression of CYP3A4 protein7q22.1
RifampinApprovedCYP3A41576
increased
Rifampin results in increased expression of CYP3A4 protein7q22.1
RifampinApprovedCYP3A41576
increased
Rifampin results in increased expression of CYP3A4 protein7q22.1