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ToxSci Advance Access published online on March 10, 2006
Toxicological Sciences, 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
Received August 22, 2005
Accepted March 2, 2006

In Vitro Toxicology

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

Mathieu Vinken 1 *, Tom Henkens 2, Tamara Vanhaecke 2, Peggy Papeleu 2, Albert Geerts 3, Elke Van Rossen 3, James Kevin Chipman 4, Paolo Meda 5, and Vera Rogiers 2

1 Department of Toxicology, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, B-1090 Brussels, Belgium; Mathieu Vinken is a doctoral research fellow of the Fund for Scientific Research Flanders (FWO-Vlaanderen), Belgium
2 Department of Toxicology, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, B-1090 Brussels, Belgium
3 Department of Cell Biology, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, B-1090 Brussels, Belgium
4 School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom
5 Department of Cell Physiology and Metabolism, CMU Université de Genève, 1 rue Michel-Servet, CH-1211 Genève 4, Switzerland

* To whom correspondence should be addressed.
Mathieu Vinken, E-mail: mvinken{at}vub.ac.be


  Abstract

BACKGROUND: The effects of the histone deacetylase inhibitor Trichostatin A (TSA) on connexin expression and gap junctional intercellular communication (GJIC) were investigated in primary cultures of adult rat hepatocytes. METHODS: GJIC was monitored by using the scrape loading/dye transfer method. Immunoblotting and immunocytochemistry were used to investigate connexin protein levels and localization. Connexin gene expression was studied by means of (q)RT-PCR. RESULTS: TSA increased Cx32 protein levels and affected negatively 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. Important to notice is that the time of onset of TSA treatment was crucial for the extent of its outcome and that the effects of TSA on connexin protein levels occurred independently of transcriptional changes. CONCLUSIONS: (i) TSA differentially affects connexin proteins in primary rat hepatocyte cultures, suggesting distinct regulation and/or distinct roles of the different connexin species in the control of hepatic homeostasis. (ii) TSA enhances GJIC between primary cultured rat hepatocytes, an interesting finding supporting its use to further optimize liver-based in vitro models for pharmaco-toxicological purposes.

Keywords: HDAC inhibitor; TSA; connexin; GJIC; primary hepatocyte culture.
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