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ToxSci Advance Access originally published online on March 10, 2006
Toxicological Sciences 2006 91(2):484-492; doi:10.1093/toxsci/kfj152
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Trichostatin A Enhances Gap Junctional Intercellular Communication in Primary Cultures of Adult Rat Hepatocytes

Mathieu Vinken*,1,2, Tom Henkens*, Tamara Vanhaecke*, Peggy Papeleu*, Albert Geerts{dagger}, Elke Van Rossen{dagger}, James Kevin Chipman{ddagger}, Paolo Meda§ and Vera Rogiers*

* Department of Toxicology, Vrije Universiteit Brussel, B-1090 Brussels, Belgium; {dagger} Department of Cell Biology, Vrije Universiteit Brussel, B-1090 Brussels, Belgium; {ddagger} School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom; and § Department of Cell Physiology and Metabolism, CMU Université de Genève, CH-1211 Genève 4, Switzerland

Received August 22, 2005; accepted March 2, 2006

The effects of histone deacetylase inhibitor Trichostatin A (TSA) on connexin (Cx) expression and gap junctional intercellular communication (GJIC) were investigated in primary cultures of adult rat hepatocytes. GJIC was monitored by using the scrape-loading/dye transfer method. Immunoblotting and immunocytochemistry were used to investigate Cx protein levels and localization. Cx gene expression was studied by means of quantitative reverse transcriptase–polymerase chain reaction. TSA increased Cx32 protein levels and affected negatively the Cx26 protein levels. The latter was preferentially located in the cytosol of cultured cells. TSA also promoted the appearance of Cx43 in the nuclear compartment of primary cultured hepatocytes. Overall, this resulted in enhanced GJIC activity. It is important to note that the time of onset of TSA treatment was crucial for the extent of its outcome and that the effects of TSA on Cx protein levels occurred independently of transcriptional changes. TSA differentially affects Cx proteins in primary rat hepatocyte cultures, suggesting distinct regulation and/or distinct roles of the different Cx species in the control of hepatic homeostasis. TSA enhances GJIC between primary cultured rat hepatocytes, an interesting finding supporting its use to further optimize liver-based in vitro models for pharmacotoxicological purposes.

Key Words: HDAC inhibitor; TSA; connexin; GJIC; primary hepatocyte culture.


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A Metabolic Screening Study of Trichostatin A (TSA) and TSA-Like Histone Deacetylase Inhibitors in Rat and Human Primary Hepatocyte Cultures
J. Pharmacol. Exp. Ther., April 1, 2007; 321(1): 400 - 408.
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