ABSTRACT
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.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/genetics , Cytochrome P-450 CYP1A2/genetics , Liver/metabolism , Mechanotransduction, Cellular/genetics , Receptors, Aryl Hydrocarbon/genetics , Cell Culture Techniques , Gene Expression Regulation/genetics , Hep G2 Cells , Hepatocytes/metabolism , Humans , Hydrostatic Pressure , Inactivation, Metabolic/genetics , Liver/drug effects , Signal Transduction/geneticsABSTRACT
Low-temperature (LT) grown GaAs has a subpicosecond carrier response time that makes it favorable for terahertz photoconductive (PC) switching. However, this is obtained at the price of lower mobility and lower thermal conductivity than GaAs. Here we demonstrate subpicosecond carrier sweep-out and over an order of magnitude higher sensitivity in detection from a GaAs-based PC switch by using a nanoplasmonic structure. As compared to a conventional GaAs PC switch, we observe 40 times the peak-to-peak response from the nanoplasmonic structure on GaAs. The response is double that of a commercial, antireflection coated LT-GaAs PC switch.
