Oxygen-mediated enhancement of primary hepatocyte metabolism, functional polarization, gene expression, and drug clearance

• DOI: 10.1073/pnas.0906820106
• Publication Date: 2009-09-01T02:09:22Z
• Authors: Srivatsan Kidambi; Rubin S. Yarmush; Eric Novik; Piyun Chao; Martin L. Yarmush; Yaakov Nahmias
• Keywords: CYP2B6; Xenobiotic

The liver is a major site for the metabolism of xenobiotic compounds due to its abundant level phase I/II metabolic enzymes. With cost drug development escalating over $400 million/drug there an urgent need rigorous models hepatic preclinical screening clearance and hepatotoxicity. Here, we present microenvironment in which primary human rat hepatocytes maintain high competence without long adaptation period. We demonstrate that co-cultures endothelial cells serum-free media seeded under 95% oxygen functional apical basal polarity, levels cytochrome P450 activity, gene expression profiles on par with freshly isolated hepatocytes. These oxygenated remarkable ability predict vivo rates both rapid slow clearing drugs R 2 0.92. Moreover, as function stabilizes overnight, testing can be carried out days or even weeks before other culture methods, significantly reducing associated labor cost. results are readily extendable configurations including three-dimensional culture, bioreactor studies, well microfabricated co-cultures.