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ToxSci Advance Access published online on March 7, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg021
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received October 17, 2002; accepted December 2, 2002
© 2003 Society of Toxicology

Molecular and Genetic Toxicology

Mechanisms of Increased Liver Tissue Repair and Survival in Diet Restricted Rats Treated with Equtoxic Doses of Thioacetamide

Udayan M. Apte 1, Pallavi B. Limaye 1, D. Desaiah 2, Thomas J. Bucci 3, Alan Warbritton 3, Harihara M. Mehendale 1*

1 Department of Toxicology, College of Pharmacy, The University of Louisiana at Monroe, Monroe, LA 71209
2 Department of Neurology, University of Mississippi Medical Center, Jackson 39216, USA
3 Pathology Associates-A Charles River Company, National Center for Toxicological Research, Jefferson, AR 72079

* To whom correspondence should be addressed. E-mail: mehendale{at}ulm.edu.


  Abstract

Moderate dietary or caloric restriction (DR) modulates animal physiology in a beneficial fashion. Previously, we have reported an equitoxic dose experiment where liver injury in DR male Sprague-Dawley rats exposed to a low dose of thioacetamide (TA, 50 mg/kg) was similar to that observed in ad libitum fed (AL) rats exposed to a 12-fold higher dose (600 mg/kg). Paradoxically, the AL rats experienced 90% mortality while all of the DR rats with the same amount of initial bioactivation-mediated liver injury survive. The protection observed in the DR rats was due to efficient compensatory liver tissue repair, which was delayed and attenuated in the AL rats leading to progression of liver injury (Ramaiah et al., Toxicol. Appl. Pharmacol. 150:12-21, 1998). The objective of the present study was to investigate the molecular mechanisms of the enhanced tissue repair in the DR rats upon equitoxic challenge with TA. Promitogenic mechanisms and mediators such as pro-inflammatory cytokines (TNF-{alpha} and IL-6), growth factors (TGF-{alpha} and HGF), and inducible nitric oxide synthase (iNOS) were estimated over a time course after equitoxic challenge (50 mg/kg to DR vs 600 mg/kg to AL rats). Except for TNF-{alpha}, all other molecules were expressed earlier and in greater amount in the DR rats. IL-6 was 10-fold greater and peaked 12 h earlier; HGF also peaked 12 h sooner in the DR rats, when it was 2.5-fold greater than the value in the AL rats. TGF-{alpha} expression in livers of DR rats increased after TA administration and peaked at 24 h while in the AL rats it was lower and peaked at 36 h. Diet restriction alone induced iNOS 2-fold in the DR animals and remained elevated until 12 h after TA administration, then declined thereafter. The lower iNOS activity in the AL rats further decreased after TA injection. DR rats exhibited higher apoptosis after thioacetamide administration, which further increased the efficiency of tissue repair. Taken together, these data indicate that even though the liver injury is near equal in AL and DR rats, sluggish signal transduction leads to delayed liver regeneration, progression of liver injury and death in the AL rats. The equitoxic dose experiment indicates that stimulation of tissue repair is independent of the extent of initial liver injury and is governed by physiology of diet restriction. DR stimulates promitogenic signaling leading to a quick and timely response upon liver injury, arrest of progressive injury on one hand and recovery from injury on the other, paving the way for survival of the DR rats.

apoptosis, HGF, IL-6, iNOS, TGF-{alpha}, tissue repair, thioacetamide .


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