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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on March 28, 2006; DOI: 10.1124/jpet.106.100933

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Received for publication January 6, 2006.
Revised March 24, 2006.
Accepted for publication March 27, 2006.

ENHANCED XENOBIOTIC-INDUCED HEPATOTOXICITY AND KUPFFER CELL ACTIVATION BY RESTRAINT-INDUCED STRESS

Sree D. Panuganti 1, Farah D. Khan 1, Craig K. Svensson 1*

1 The University of Iowa

* Address correspondence to: E-mail: craig-svensson{at}uiowa.edu

Abstract

We tested the hypothesis that environmental stress is a predisposing factor for liver injury by examining the effect of acute restraint on liver injury provoked by carbon tetrachloride (CCl4) and allyl alcohol. Mice were immobilized using Plexiglas® restraint cages, producing a form of psychogenic stress, while other animals were allowed to roam free. Serum alanine aminotransferase (ALT) levels were elevated significantly in restrained animals after administration of varying doses of CCl4 or allyl alcohol that did not produce liver injury in unrestrained animals. This enhanced liver injury after CCl4 was seen in both male and female mice. The duration of acute restraint was found to be important, as a period of 2.5 h of restraint enhanced hepatotoxicity, while shorter periods of restraint did not significantly increase liver injury. Serum corticosterone concentrations increased, while hepatic glutathione (GSH) content decreased, during and following acute restraint. In addition, delay in administration of CCl4 until 5 h after completion of restraint also produced an elevated level of liver injury compared to that seen in free roaming animals. Immunohistochemical examination of the livers showed significantly enhanced Kupffer cell activation in restrained mice compared to that of free roaming mice. These observations suggest that induction of psychogenic stress may increase the susceptibility to liver injury observed with classic hepatotoxicants and may represent an important predisposing factor to liver injury following xenobiotic exposure. The underlying mechanism appears to be increased macrophage activation in the liver, which may subsequently sensitize hepatocytes to xenobiotics and thus enhance hepatotoxicity.


Key words: Kupffer cells, allyl alcohol, carbon tetrachloride, hepatotoxicity, restraint, stress


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