Abstract 3545: Glucose-dependent regulation of PXR is modulated by AMPK

Abstract

Abstract The sensitivity of patients to drugs depends on the pharmacokinetics of the drugs, but largely on the bioavailability of the drugs in the body. Orally administered drugs must pass through the intestinal wall and the portal circulation to reach the liver; both are sites of first-pass metabolism. Thus, many drugs may be metabolized before optimal plasma concentrations are reached, or before getting to target tissues, resulting in diminished drug efficacy and acquired drug resistance. Among the several drug-metabolizing enzymes (DME) is cytochrome P450 (CYP) enzyme 3A4, the most abundant in the liver, metabolizes approximately 50 percent of marketed drugs and a main target of pregnane X receptor (PXR) In addition, transporters including MDR1 are also regulated by PXR. There is increasing evidence that drug metabolism can be affected by energy metabolism and vice versa. PXR has been implicated to have a complex role in energy homeostasis, and increased drug clearance was observed in untreated diabetic patients. The elimination of any chemotherapeutic agents in humans is markedly dependent on the relative expression and activity of the various DMEs and drug transpoters. The heterotrimeric AMP-activated protein kinase (AMPK) serves as a monitor of cellular energy status in most eukaryotic cell, and is activated under energy stress conditions. Interestingly, AMPK is also regarded as a tumor suppressor in various cancers because of its inhibitory effects on anabolic processes that are important for tumor development. Despite the knowledge of the cross-regulation between drug metabolism and energy metabolism, the molecular pathways of this interaction remain vague. In our study, we exposed HepG2 cells to varying glucose concentrations and observed that PXR is greatly induced in high glucose conditions. This finding is consistent with clinical observation of increased drug clearance in untreated diabetic patients. We demonstrate that AMPK modulates PXR transcriptional activity. As such, the pharmacological manipulations of AMPK activation status show an inverse relationship with PXR activity. Activation of AMPK was shown to decrease PXR activity as observed by decreased CYP3A4 transcription, and consistent with that a potentiation of response to drugs. Interestingly, we observed that PXR is not a direct target of AMPK: it remains to be determined what the intermediary between AMPK and PXR is. Taken together, our studies identify novel links between the energy status of the cell, the activation of AMPK and down regulation of PXR. Citation Format: Peter O. Oladimeji. Glucose-dependent regulation of PXR is modulated by AMPK [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3545. doi:10.1158/1538-7445.AM2017-3545