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

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. 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. Paclitaxel, erlotinib, tamoxifen, ifosfamide, flutamide and docetaxel are able to activate PXR, while only strong PXR activation leads to significant induction of CYP3A4 activity. The identified PXR agonists may have the propensity to cause clinically relevant drug-drug interactions as a result of CYP3A4 induction.

Citation

S Harmsen, I Meijerman, J H Beijnen, J H M Schellens. Nuclear receptor mediated induction of cytochrome P450 3A4 by anticancer drugs: a key role for the pregnane X receptor. Cancer chemotherapy and pharmacology. 2009 Jun;64(1):35-43

Mesh Tags

Substances

PMID: 18839173

search → result