A cell lines derived microfluidic liver model for investigation of hepatotoxicity induced by drug-drug interaction

Abstract

The poor metabolic ability of cell lines fails to meet the requirements of an in vitro model for drug interaction testing which is crucial for the development or clinical application of drugs. Herein, we describe a liver sinusoid-on-a-chip device composed of four kinds of transformed cell lines (HepG2 cells, LX-2 cells, EAhy926 cells, and U937 cells) that were ordered in a physiological distribution with artificial liver blood flow and biliary efflux flowing in the opposite direction. This microfluidic device applied three-dimensional culturing of HepG2 cells with high density (10 7  ml −1 ), forming a tightly connected monolayer of EAhy926 cells and achieving the active transport of drugs in HepG2 cells. Results showed that the device maintained synthetic and secretory functions, preserved cytochrome P450 1A1/2 and uridine diphosphate glucuronyltransferase enzymatic activities, as well as sensitivity of drug metabolism. The cell lines derived device enables the investigation of a drug-drug interaction study. We used it to test the hepatotoxicity of acetaminophen and the following combinations: “acetaminophen + rifampicin,” “acetaminophen + omeprazole,” and “acetaminophen + ciprofloxacin.” The variations in hepatotoxicity of the combinations compared to acetaminophen alone, which is not found in a 96-well plate model, in the device were −17.15%, 14.88%, and −19.74%. In addition, this result was similar to the one tested by the classical primary hepatocyte plate model (−13.22%, 13.51%, and −15.81%). Thus, this cell lines derived liver model provides an alternative to investigate drug hepatotoxicity, drug-drug interaction.