TY - GEN A1 - Kammerer, Sarah A1 - Nowak, Elisabeth A1 - Mantke, René A1 - Jung, Friedrich A1 - Küpper, Jan-Heiner T1 - 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 T2 - Clinical Hemorheology and Microcirculation N2 - 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. KW - Liver biotransformation KW - first-pass effect KW - CYP3A4 KW - MG-132 KW - cancer cells KW - in vitro culture systems Y1 - 2024 UR - https://opus4.kobv.de/opus4-UBICO/frontdoor/index/index/docId/32259 UR - https://content.iospress.com/articles/clinical-hemorheology-and-microcirculation/ch238108 SN - 1386-0291 VL - 86 IS - 1-2 SP - 159 EP - 168 ER -