Picture of UK Houses of Parliament

Leading national thinking on politics, government & public policy through Open Access research

Strathprints makes available scholarly Open Access content by researchers in the School of Government & Public Policy, based within the Faculty of Humanities & Social Sciences.

Research here is 1st in Scotland for research intensity and spans a wide range of domains. The Department of Politics demonstrates expertise in understanding parties, elections and public opinion, with additional emphases on political economy, institutions and international relations. This international angle is reflected in the European Policies Research Centre (EPRC) which conducts comparative research on public policy. Meanwhile, the Centre for Energy Policy provides independent expertise on energy, working across multidisciplinary groups to shape policy for a low carbon economy.

Explore the Open Access research of the School of Government & Public Policy. Or explore all of Strathclyde's Open Access research...

Human hepatic HepaRG cells maintain an organotypic phenotype with high intrinsic CYP450 activity/metabolism and significantly outperform standard HepG2/C3A cells for pharmaceutical and therapeutic applications

Nelson, Leonard J. and Morgan, Katie and Treskes, Philipp and Samuel, Kay and Henderson, Catherine J. and LeBled, Claire and Homer, Natalie and Grant, M. Helen and Hayes, Peter C. and Plevris, John N. (2017) Human hepatic HepaRG cells maintain an organotypic phenotype with high intrinsic CYP450 activity/metabolism and significantly outperform standard HepG2/C3A cells for pharmaceutical and therapeutic applications. Basic and Clinical Pharmacology and Toxicology, 120 (1). pp. 30-37. ISSN 1742-7835

[img]
Preview
Text (Nelson-etal-BCPT-2016-Human-hepatic-HepaRG-cells-maintain-an-organotypic-phenotype)
Nelson_etal_BCPT_2016_Human_hepatic_HepaRG_cells_maintain_an_organotypic_phenotype.pdf
Accepted Author Manuscript

Download (3MB)| Preview

    Abstract

    Conventional in vitro human hepatic models for drug testing are based on the use of standard cell lines derived from hepatomas or primary human hepatocytes (PHHs). Limited availability, inter-donor functional variability and early phenotypic alterations of PHHs restrict their use; whilst standard cell lines such as HepG2 lack a substantial and variable set of liver-specific functions such as CYP450 activity. Alternatives include the HepG2-derivative C3A cells selected as a more differentiated and metabolically active hepatic phenotype. Human HepaRG cells are an alternative organotypic co-culture model of hepatocytes and cholangiocytes reported to maintain in vivo-like liver-specific functions, including intact Phase 1-3 drug metabolism. In this study, we compared C3A and human HepaRG cells using phenotypic profiling, CYP450 activity and drug metabolism parameters to assess their value as hepatic models for pre-clinical drug testing or therapeutics. Compared with C3As, HepaRG co-cultures, exhibit a more organotypic phenotype, including evidence of hepatic polarity with strong expression of CYP3A4, the major isoform involved in the metabolism of over 60% of marketed drugs. Significantly greater CYP450 activity and expression of CYP1A2, CYP2E1 and CYP3A4 genes in HepaRG cells (comparable with that of human liver tissue) was demonstrated. Moreover, HepaRG cells also preferentially expressed the hepatic integrin α5β1 – an important modulator of cell behaviour including growth and survival, differentiation and polarity. Drug metabolite profiling of phenacetin (CYP1A2) and testosterone (CYP3A4) using LC-MS/MS and HPLC, respectively, revealed HepaRGs had more intact (Phase 1-2) metabolism profile. Thus, HepaRG cells significantly outperform C3A cells for potential pharmaceutical and therapeutic applications.