Bioactivation and Toxicity of Acetaminophen in a Rat Hepatocyte Micropatterned Coculture System

Authors


  • Contract Grant Sponsor: Long-Range Research Initiative of the American Chemistry Council, Washington, DC 20002, U.S.A.

Correspondence to: Salman R. Khetani.

ABSTRACT

We have recently shown that primary rat hepatocytes organized in micropatterned cocultures with murine embryonic fibroblasts (HepatoPac™) maintain high levels of liver functions for at least 4 weeks. In this study, rat HepatoPac was assessed for its utility to study chemical bioactivation and associated hepatocellular toxicity. Treatment of HepatoPac cultures with acetaminophen (APAP) over a range of concentrations (0–15 mM) was initiated at 1, 2, 3, or 4 weeks followed by the assessment of morphological and functional endpoints. Consistent and reproducible concentration-dependent effects on hepatocyte structure, viability, and basic functions were observed over the 4-week period, and were exacerbated by depleting glutathione using buthionine sulfoximine or inducing CYP3A using dexamethasone, presumably due to increased reactive metabolite-induced stress and adduct formation. In conclusion, the results from this study demonstrate that rat HepatoPac represents a structurally and functionally stable hepatic model system to assess the long-term effects of bioactivated compounds. © 2013 Wiley Periodicals, Inc. J BiochemMol Toxicol 27:471-478, 2013; View this article online at wileyonlinelibrary.com. DOI 10.1002/jbt.21512

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