In vitro simulation of the liver first-pass effect with biotransformation-competent HepG2 cells to study effects of MG-132 on liver and cancer cells
Issue title: Selected articles from the 3rd Joint Meeting of The European Society for Clinical Hemorheology and Microcirculation (ESCHM) , The International Society for Clinical Hemorheology (ISCH) and The International Society of Biorheology (ISB), Regensburg, Germany, 28 – 30 September 2023
Guest editors: L. Prantl, A. Krueger-Genge and F. Jung
Affiliations: [a] Institute of Biotechnology, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany
| [b] Department of General Surgery, University Hospital Brandenburg, Brandenburg Medical School Theodor Fontane, Brandenburg an der Havel, Germany
| [c] MVZ Gemeinschaftslabor Cottbus, Cottbus, Germany
Correspondence:
[*]
Corresponding author: Sarah Kammerer, Institute of Biotechnology, Brandenburg University of Technology Cottbus-Senftenberg, Universitätsplatz 1, 01968 Senftenberg, Germany. Tel.: +49 357385934; E-mail: [email protected].
Abstract: BACKGROUND: Liver biotransformation is the major route for drug metabolism in humans, often catalysed by cytochrome P450 (CYP) enzymes. This first-pass effect can lead to hepatotoxicity and influences the bioavailability of drugs. OBJECTIVE: We aimed to establish in vitro culture systems simulating the liver first-pass to study effects of the proteasome inhibitor MG-132 simultaneously on hepatocytes and cancer cells. METHODS: The first-pass effect was simulated by conditioned medium transfer (CMT) from pre-treated HepG2 CYP3A4-overexpressing cells to either pancreatic cancer cell line PANC-1 or primary colon cancer cells, and by indirect co-culture (CC) of liver and cancer cells in a shared medium compartment. Experimental proteasome inhibitor MG-132 was used as test substance as it is detoxified by CYP3A4. RESULTS: Cancer cells showed higher viabilities in the first-pass simulation by CMT and CC formats when compared to monocultures indicating effective detoxification of MG-132 by HepG2 CYP3A4-overexpressing cells. HepG2-CYP3A4 cells showed reduced viabilites after treatment with MG-132. CONCLUSIONS: We successfully established two different culture systems to simulate the liver first-pass effect in vitro. Such systems easily allow to study drug effects simultaneously on liver and on target cancer cells. They are of great value in pre-clinical cancer research, pharmaceutical research and drug development.
Keywords: Liver biotransformation, first-pass effect, CYP3A4, MG-132, cancer cells, in vitro culture systems
