Hydrostatic pressure regulates CYP1A2 expression in human hepatocytes via a mechanosensitive aryl hydrocarbon receptor-dependent pathway
Autor: | Lynn Abernethy, Lewis Burton, Paula J. Scaife, Peter Littlewood, Howard R. Mellor, Cyril Rauch, Stuart W. Paine |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Physiology Hydrostatic pressure Cell Culture Techniques Mechanotransduction Cellular 03 medical and health sciences 0302 clinical medicine Mechanosensitivity drug metabolism hepatocytes cell Biology physiology Cytochrome P-450 CYP1A2 In vivo Basic Helix-Loop-Helix Transcription Factors Hydrostatic Pressure medicine Humans biology Chemistry mechanosensitivity Hep G2 Cells Cell Biology Aryl hydrocarbon receptor drug metabolism In vitro Cell biology 030104 developmental biology medicine.anatomical_structure Gene Expression Regulation Liver Receptors Aryl Hydrocarbon Cell culture Hepatocyte Inactivation Metabolic Hepatocytes biology.protein Mechanosensitive channels 030217 neurology & neurosurgery Drug metabolism Research Article Signal Transduction |
Zdroj: | American Journal of Physiology-Cell Physiology |
ISSN: | 1522-1563 0363-6143 |
DOI: | 10.1152/ajpcell.00472.2019 |
Popis: | Approximately 75% of xenobiotics are primarily eliminated through metabolism; thus the accurate scaling of metabolic clearance is vital to successful drug development. Yet, when data is scaled from in vitro to in vivo, hepatic metabolic clearance, the primary source of metabolism, is still commonly underpredicted. Over the past decades, with biophysics used as a key component to restore aspects of the in vivo environment, several new cell culture settings have been investigated to improve hepatocyte functionalities. Most of these studies have focused on shear stress, i.e., flow mediated by a pressure gradient. One potential conclusion of these studies is that hepatocytes are naturally “mechanosensitive,” i.e., they respond to a change in their biophysical environment. We demonstrate that hepatocytes also respond to an increase in hydrostatic pressure that, we suggest, is directly linked to the lobule geometry and vessel density. Furthermore, we demonstrate that hydrostatic pressure improves albumin production and increases cytochrome P-450 (CYP) 1A2 expression levels in an aryl hydrocarbon-dependent manner in human hepatocytes. Increased albumin production and CYP function are commonly attributed to the impacts of shear stress in microfluidic experiments. Therefore, our results highlight evidence of a novel link between hydrostatic pressure and CYP metabolism and demonstrate that the spectrum of hepatocyte mechanosensitivity might be larger than previously thought. |
Databáze: | OpenAIRE |
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