Camptothecin attenuates cytochrome P450 3A4 induction by blocking the activation of human pregnane X receptor.
Differential regulation of drug-metabolizing enzymes (DMEs) is a common cause of adverse drug effects in cancer therapy. Due to the extremely important role of cytochrome P450 3A4 (CYP3A4) in drug metabolism and the dominant regulation of human pregnane X receptor (hPXR) on CYP3A4, finding inhibitors for hPXR could provide a unique tool to control drug efficacies in cancer therapy. Camptothecin (CPT) was demonstrated as a novel and potent inhibitor (IC(50) = 0.58 microM) of an hPXR-mediated transcriptional regulation on CYP3A4 in this study. In contrast, one of its analogs, irinotecan (CPT-11), was found to be an hPXR agonist in the same tests. CPT disrupted the interaction of hPXR with steroid receptor coactivator-1 but had effects on neither the competition of ligand binding nor the formation of the hPXR and retinoid X receptor alpha heterodimer, nor the interaction between the regulatory complex and DNA-responsive elements. CPT treatment resulted in delayed metabolism of nifedipine in human hepatocytes treated with rifampicin, suggesting a potential prevention of drug-drug interactions between CYP3A4 inducers and CYP3A4-metabolized drugs. Because CPT is the leading compound of topoisomerase I inhibitors, which comprise a quickly developing class of anticancer agents, the findings indicate the potential of a new class of compounds to modify hPXR activity as agonists/inhibitors and are important in the development of CPT analogs.
Chen
Yakun
Y
Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine and SimmonsCooper Cancer Institute, Springfield, IL 62794-9626, USA.
Tang
Yong
Y
Robbins
Gregory T
GT
Nie
Daotai
D
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D015153:Blotting, Western; D002166:Camptothecin / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis; D065692:Cytochrome P-450 CYP3A Inhibitors; D024202:Electrophoretic Mobility Shift Assay; D004790:Enzyme Induction / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D009543:Nifedipine / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D000077297:Pregnane X Receptor; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D011987:Receptors, Steroid / Q000037:antagonists & inhibitors*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000972:Antineoplastic Agents, Phytogenic; D065692:Cytochrome P-450 CYP3A Inhibitors; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D012313:RNA; D008156:Luciferases; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D009543:Nifedipine; D002166:Camptothecin