Abstract
Primary hepatocytes have been used in drug development for the evaluation of hepatotoxicity of candidate compounds. However, the rapid depression of their hepatic characters in vitro must be improved to predict toxicity with higher accuracy. We have hypothesized that a well organized tissue construct that includes nonparenchymal cells and appropriate scaffold material(s) could overcome this difficulty by remediating the viability and physiological function of primary hepatocytes. In this study, we constructed an in vitro liver tissue model, consisting of mouse primary hepatocytes assembling around an endothelial cell network on Engelbreth-Holm-Swarm gel, and examined its response to acetaminophen treatment. The increase in lactate dehydrogenase release after the exposure to acetaminophen was induced earlier in the liver tissue model than in monolayer hepatocytes alone, suggesting that the tissue model was more sensitive to an acetaminophen-induced toxicity. On the basis of our results, we conclude that liver tissue models of this kind may enhance the responses of hepatocytes against xenobiotics via the maintenance of hepatic genes and functions such as cytochrome P450s. These findings will contribute to the development of more accurate systems for evaluating hepatotoxicity.
Footnotes
This work was supported by the Precursory Research for Embryonic Science and Technology and the Adaptable and Seamless Technology transfer Program through target-driven R&D funding [Grant AS2211513G] from the Japan Science and Technology Agency (JST); a Grant-in-Aid for Scientific Research (B) [Grant 21300178] from the Japanese Society for the Promotion of Science (JSPS); and a Grant-in-Aid for Scientific Research on Innovative Areas [Grant 23119003] from the Ministry of Education, Culture, Sports, Science and Technology. Y.To. and M.T. are JSPS research fellows.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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ABBREVIATIONS:
- ECM
- extracellular matrix
- ES
- embryonic stem
- IVLmES
- mouse ES cell-derived in vitro liver tissue model
- HUVEC
- human umbilical vein endothelial cell
- NAPQI
- N-acetyl-p-benzoquinone imine
- IVL
- in vitro liver model
- APAP
- N-(4-hydroxyphenyl)acetamide
- EHS
- Engelbreth-Holm-Swarm
- OHT
- hydroxytestosterone
- HP
- hydroxyprogesterone
- EGM-2
- endothelial cell growth medium-2
- DMEM
- Dulbecco's modified Eagle's medium
- HBSS
- Hank's balanced salt solution
- LDH
- lactate dehydrogenase
- HPLC
- high-performance liquid chromatography
- CE-TOFMS
- capillary electrophoresis coupled with electrospray ionization time-of-flight mass spectrometry
- PECAM-1
- platelet endothelial cell adhesion molecule-1
- vWF
- Von Willebrand factor
- HGF
- hepatocyte growth factor
- IVLEHS
- in vitro liver model on EHS gel
- RT-PCR
- reverse transcription-polymerase chain reaction
- hprt
- hypoxanthine-guanine phosphoribosyltransferase
- TAT
- tyrosine aminotransferase.
- Received June 10, 2011.
- Accepted October 18, 2011.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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