Vinorelbine Inhibits Pregnane X Receptor‐Mediated Induction of Cytochrome P450 3A4 Gene Expression in Human Hepatocytes

Abstract

Pregnane X receptor (PXR), a ligand‐dependent nuclear receptor, is involved in regulating the gene expression of enzymes and proteins involved in endobiotic and xenobiotic metabolism. In particular, PXR plays a crucial role in regulating the gene expression of drug‐metabolizing enzymes, including cytochrome p450 3A4 (CYP3A4). In cancer patients, upregulation of the PXR target genes, including CYP3A4, can lead to not only adverse drug interactions but also chemoresistance. It is possible to inhibit the activity of PXR in order to overcome PXR‐mediated adverse drug interactions and chemoresistance. In this regard, a few PXR inhibitors or antagonists have been identified and characterized. However, these compounds fall short of reaching their clinical utility as they are non‐selective and/or highly‐toxic. Therefore, there is a practical need to develop a selective and less‐toxic PXR antagonist to overcome PXR‐mediated adverse drug interactions and chemoresistance. We sought to determine whether vinorelbine (VNB), a clinically‐used antimicrotubule agent, inhibits the transcriptional activity of PXR in human hepatocytes. PXR transactivation and cell viability assays were performed to determine CYP3A4 promoter activity and cytotoxicity, respectively, in HepG2 human liver carcinoma cells. Quantitative RT‐PCR assays were conducted to study gene expression of CYP3A4 in human primary hepatocytes. VNB, at its non‐cytotoxic and therapeutically‐relevant concentrations, inhibited PXR transactivation of CYP3A4 promoter activity. Additionally, VNB attenuated the PXR agonist‐induced gene expression of CYP3A4, suggesting that VNB downregulates CYP3A4 gene expression by inhibiting the activity of PXR. These results support our conclusion that VNB inhibits the transcriptional activity of PXR at its non‐cytotoxic and therapeutically relevant concentrations. Future studies will be directed to study the selectivity of VNB to PXR as well as the mechanisms of VNB inhibition of PXR‐mediated CYP3A4 induction.Support or Funding InformationThis work was supported by the Auburn University Research Initiative in Cancer Grant, Animal Health and Disease Research Grant, and Auburn University Startup Funds to Pondugula SR. The authors would like to thank Drs. Coleman, Tao, and Schwartz for sharing their research facilities.