Abstract 2667: Inhibition of CYP3A4 expression by camptothecin via blocking activation of pregnane X receptor

Abstract

Abstract Individual variation in drug metabolism is a major cause of unpredictable side effects during cancer therapy. Drug metabolism is controlled by a class of orphan nuclear receptors (NRs), which regulate the expression of cytochrome 3A4 (CYP3A4), an enzyme metabolizing more than 60% of clinically used drugs. In our study, it was found that xenobiotic-mediated induction of CYP3A4 gene expression in primary human hepatocytes was inhibited by camptothecin (CPT) but not by its analogue, irinotecan (CPT-11). CPT exerted its effect by inhibiting the activation of NR, human pregnenolone X receptor (hPXR). In contrast, irinotecan was found to be an hPXR agonist in the same tests. CPT disrupted the interaction of hPXR with steroid receptor coactivator-1 (SRC-1) but had no effects on the formation of the hPXR and retinoid X receptor α (RXRα) heterodimer. Nor had it effects on the interactions between the regulatory complex and DNA responsive elements. CPT treatment resulted in delayed metabolism of nifedipine induced by rifampicin in human hepatocytes, suggesting a potential drug-drug interaction (DDI) between CPT and CYP3A4 metabolized drugs. The study found a novel potent hPXR antagonist and indicated the potential of a new class of compounds to control drug efficacies in cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2667.