Camptothecin Attenuates Cytochrome P450 3A4 Induction by Blocking the Activation of Human Pregnane X Receptor

Abstract

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 ϭ 0.58 M) 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 ␣ 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.Topoisomerase I inhibitors are a quickly developing class of anticancer agents. Clinical trials with the leading compound of this class of drugs, camptothecin (CPT), showed remarkable anticancer activity by interrupting DNA replication in cancer cells (Chen and Liu, 1994). Several semisynthetic derivatives of CPT, such as topotecan and irinotecan (CPT-11), have been used in cancer chemotherapy (Creemers et al., 1994). Although the main mechanism by which topoisomerase I inhibitors produce their antitumor effects has been widely investigated, both the mechanism of interindividual variability in the plasma disposition and the potential to regulate the efficacy of other compounds when used in combination are not fully understood (van Warmerdam et al., 1996).Up-regulation/down-regulation of drug-metabolizing enzymes (DMEs) is a common cause of unpredictable drug effects during cancer therapy (Rochat, 2005), especially the alteration in the expression of cytochrome P450 3A4 (CYP3A4), an enzyme involved in the metabolism of 60% of drugs (Guengerich, 1999), including many anticancer drugs. Hu- ABBREVIATIONS: CPT, camptothecin; DME, drug-metabolizing enzyme; hPXR, human pregnane X receptor; DDI, drug-drug interaction; SRC-1, steroid receptor cofactor-1; 1,25-(OH) 2 VD 3 , 1␣, 25-dihydroxyvitamin D3; CITCO,

Milk Thistle’s Active Components Silybin and Isosilybin: Novel Inhibitors of PXR-Mediated CYP3A4 Induction

“…However, this treatment is not always successful and often unwanted pharmacological effects occur in cancer patients, such as unresponsiveness or toxicity. A common cause for these unpredictable effects is up and down regulation of drug transporters or drug-metabolizing enzymes such as cytochrome P450 (Harmsen et al, 2009;Chen et al, 2010). Of these enzymes, CYP3A4 is quantitatively the most important because it metabolizes more than 50% of all drugs and the majority of the currently prescribed anticancer drugs (Anzenbacher and Anzenbacherová, 2001).…”

Effect of the CYP3A inhibitor ketoconazole on the PXR-mediated induction of CYP3A activity

“…This mechanism has been described for ketoconazole [4], fluconazole [5], camptothecin [6] and a novel human immunodeficiency virus protease inhibitor [7] and has also been suggested for the diseasemodifying antirheumatic drug leflunomide [8]. In these studies, ketoconazole was shown to disrupt the binding of coregulators (including co-activators and co-repressors) to PXR in an agonist-dependent fashion [4].…”

Pregnane X receptor and drug-induced liver injury

“…Vast efforts have been made to develop analogs that address these drawbacks. Some of these analogs activate PXR, including irinotecan [101] and topotecan [102], which is in line with the fact that the ligand cavity is very flexible and may be able to accommodate structurally similar molecules in various orientations [103]. As a matter of fact, the agonist SR12813 occupies the ligand pocket in multiple orientations [104], but it is fixed in a single distinct position upon co-activator binding [105].…”