Development of an in vitro model for the study of drug-induced bile acid synthesis and transport dysfunction in a 3-D tissue engineered liver microreactor culturing system

TOXI 45

J. Ricardo Llamas Vidales, rllamas@mit.edu1, Ju Liu, juliu@mit.edu1, Jung Nyun Kim1, Sharon Karackattu1, Michal Bokayza1, Keith Hoffmaster, Keith.A.Hoffmaster@pfizer.com2, Steve R. Tannenbaum, srt@mit.edu3, and Linda G. Griffith, griff@mit.edu4. (1) Biological Engineering Division, Massachusetts Institute of Technology, 77 Massachusetts Ave., Cambridge, MA 02139, (2) Pfizer Research Technology Center, 620 Memorial Dr, Cambridge, MA 02139, (3) Division of Biological Engineering, Massachusetts Institute of Technology, 56-731, 77 Massachusetts avenue, Cambridge, MA 02139, (4) Department of Chemical and Biological Engineering, Center for Biomedical Engineering, and Biotechnology Process Engineering Cent, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Room 66-466, Cambridge, MA 02139
Drug-induced bile acid synthesis and transport dysfunction studies in in vitro liver cultures are difficult to conduct with current widely-used in vitro models due in part to rapid dedifferentiation of primary hepatocytes in culture. A 3D liver microreactor system was developed with the goal of maintaining hepatic functions in long-term primary hepatocyte cultures. Microreactor primary rat hepatocyte culture bile acid synthesis rates have been measured to be closer to physiological and much higher than that of hepatocyte cultures in widely-used in vitro models. Taurocholic acid accumulation data suggests these cultures preserve twice the bile acid transport activity than widely-used in vitro models. Accumulation data also suggests microreactor cultures develop functioning bile canaliculi-like structures, consistent with imaging data. Future work focuses on measuring effects of cholestasis-inducing compounds on bile acid transport and synthesis kinetics, as well as its effect on expression of relevant transporters and enzymes.
 

Poster Session and Awards
6:00 PM-10:00 PM, Tuesday, August 21, 2007 BCEC -- 204 A/B, Poster

Division of Chemical Toxicology

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007