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ToxSci Advance Access published online on December 8, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfi052
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Toxicological Sciences © Society of Toxicology 2004; all rights reserved.
Received October 8, 2004
Accepted December 6, 2004

In Vitro Toxicology

In Vitro Zonation and Toxicity in a Perfused Hepatocyte Co-Culture

Jared W. Allen 1, Salman R. Khetani 1, and Sangeeta N. Bhatia 1*

1 Department of Bioengineering, University of California at San Diego, La Jolla, CA; Department of Medicine, University of California at San Diego, La Jolla, CA

* To whom correspondence should be addressed.
Sangeeta N. Bhatia, E-mail: sbhatia{at}ucsd.edu


  Abstract

In vitro models that more closely represent the intricate architecture and functional diversity of the liver would be beneficial to toxicology. We have established a bioreactor culture system that recapitulates features of liver zonation in vitro, allowing investigation of compartmentalized drug metabolism and toxicity. In vitro zonation is induced by exposing hepatocyte cultures to oxygen and nutrient gradients in a parallel plate bioreactor. Gradients were modeled and experimentally validated over co-cultures of hepatocytes and fibroblasts that exhibit a stable hepatocyte phenotype in vitro. Co-cultures exposed to physiologic oxygen gradients exhibited zonal induction of CYP2B and CYP3A protein that mimics that found in vivo. Furthermore, exposure to a prototypic zonal hepatotoxin, APAP, resulted in maximal toxicity at the low-oxygen outlet region similar to centrilobular necrotic patterns observed in vivo. In conclusion, we have established a perfused hepatocyte co-culture system for molecular and applied investigation into zonation-dependent phenomena involving drug metabolism and toxicity.

Keywords: in vitro models; liver zonation; acetaminophen; cytochrome P450 induction; hepatocyte bioreactor.
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