Nuclear receptor mediated induction of cytochrome P450 3A4 by anticancer drugs: a key role for the pregnane X receptor.
OBJECTIVE
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.
Department of Pharmaceutical Sciences, Division of Biomedical Analysis, Faculty of Science, Utrecht University, Utrecht, The Netherlands. s.harmsen@uu.nl
S
S
Harmsen
I
I
Meijerman
J H
JH
Beijnen
J H M
JH
Schellens
D000230:Adenocarcinoma / Q000201:enzymology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000201:enzymology; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis / Q000187:drug effects*; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D008874:Midazolam / Q000378:metabolism; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000378:metabolism; D011987:Receptors, Steroid / Q000819:agonists*
D000970:Antineoplastic Agents; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D011987:Receptors, Steroid; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam