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Modulation of adopted nuclear receptors, pregnane X receptor (PXR) and constitutive androstane receptor (CAR), by commonly prescribed chemotherapy agents
Author(s) -
Lockhart A. C.,
Lee W.,
Ingram A. D.,
Lee K. A.,
Kim R. B.
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2003.11.194
Subject(s) - pregnane x receptor , constitutive androstane receptor , pharmacology , cyp3a4 , etoposide , cisplatin , camptothecin , chemistry , nuclear receptor , biology , chemotherapy , medicine , transcription factor , biochemistry , cytochrome p450 , enzyme , gene
The adopted nuclear receptors (NRs), CAR and PXR are key regulators of genes involved in drug disposition and may contribute to variable drug response and toxicity. Currently, little is known regarding the contribution of the NRs to chemotherapy‐associated drug interactions or toxicities. We utilized a cell‐based reporter assay to identify potential novel interactions between PXR or CAR and commonly prescribed chemotherapy drugs. In single agent studies, CAR‐dependent activation of the CYP3A4 promoter was enhanced by vinblastine (EC 50 =28.6 nM) and CPT‐11 (EC 50 =16.9 μM). Conversely, camptothecin (CPT) appeared to inhibit CAR activation (IC 50 =0.34 μM). CPT and cisplatin did not exert any effects as single agents; however both agents appeared to attenuate rifampin‐mediated PXR activation in a dose‐dependent manner, suggesting those agents may be antagonists of PXR. Interestingly, rifampin‐mediated PXR activation was further enhanced by the co‐incubation with etoposide or CPT‐11. In primary human hepatocytes, rifampin‐mediated CYP3A induction was similarly attenuated by the co‐incubation with CPT and cisplatin, suggesting that NR‐based reporter assays may be a useful tool for predicting conditions in vivo. Overall, our studies demonstrate that NRs interact with a number of commonly prescribed chemotherapy agents and that certain combination regimens may modulate NRs in an unexpected manner and contribute to the observed variability in efficacy and toxicity. Clinical Pharmacology & Therapeutics (2004) 75 , P51–P51; doi: 10.1016/j.clpt.2003.11.194