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ToxSci Advance Access published online on October 20, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfi012
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received June 7, 2004
Accepted September 7, 2004

In Vitro Toxicology

Signaling Modulation of Bile Salt-Induced Necrosis in Isolated Rat Hepatocytes

Mariana Borgognone 1, Leonardo M. Pérez 1, Cecilia L. Basiglio 1, Justina E. Ochoa 1, and Marcelo G. Roma 1*

1 Institute of Experimental Physiology, CONICET-University of Rosario, Rosario (S2002LRL), Argentina

* To whom correspondence should be addressed.
Marcelo G. Roma, E-mail: mroma{at}fbioyf.unr.edu.ar


  Abstract

Hydrophobic bile salts induce either necrosis or apoptosis depending on the severity of the injury caused by them. Since bile salt-induced apoptosis is influenced by Ca2+- and protein kinase-signaling pathways, and both necrosis and apoptosis share common initiating mechanisms, we analyzed whether these signaling cascades also influence bile salt-induced necrosis in isolated rat hepatocytes. Taurochenodeoxycholate (TCDC, 0.25-1.50 mM, 2 h) reduced, in a dose-dependent manner, the percentage of viable hepatocytes, and increased the release of the cytosolic enzyme, lactate dehydrogenase (LDH) and alanine aminotransferase (ALAT), and that of the plasma membrane enzyme, alkaline phosphatase (AP). The PKC inhibitors, H7 (100 µM) and chelerythrine (2.5 µM), both prevented significantly TCDC-induced necrosis. On the contrary, the PKA activator, dibutyryl-cAMP, exacerbated TCDC-induced cell damage in a dose-dependent manner; this effect was more likely due to cAMP-mediated PKA activation, as the PKA inhibitor, KT5720 (1 µM), counteracted this effect. Instead, the intracellular Ca2+ chelator, BAPTA/AM (20 µM), was without effect. TCDC (1 mM) increased lipid peroxidation from 0.7±0.2 to 7.5±0.9 nmol of malondialdehyde per mg of protein, p<0.001; the addition of the free radical scavenger, diphenyl-p-phenylendiamine, completely blocked this increase and prevented significantly TCDC-induced necrosis. PKC inhibition induced only a slight attenuation of TCDC-induced lipid peroxidation. Possible mechanisms accounting for the modulatory effect of signal transduction pathways on TCDC-induced necrosis, including signaling influence on TCDC transport events and TCDC-induced oxidative stress, are discussed.

Keywords: Cytosolic calcium; hepatocyte; hydrophobic bile salt; necrosis; oxidative stress; protein kinase.
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