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ToxSci Advance Access published online on April 15, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg059
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received November 21, 2002; accepted February 7, 2003
© 2003 Society of Toxicology

Biotransformation and Toxicokinetics

Type I Diabetic Mice Are Protected from Acetaminophen Hepatotoxicity

Kartik Shankar 1, Vishal S. Vaidya 1, Udayan M. Apte 1, Jose E. Manautou 2, Martin J.J. Ronis 3, Thomas J. Bucci 4, Harihara M. Mehendale 1*

1 Department of Toxicology, School of Pharmacy, The University of Louisiana at Monroe, LA 71209, USA
2 Department of Pharmaceutical Sciences, College of Pharmacy, University of Connecticut, Storrs, CT 06269, USA
3 Arkansas Children's Hospital Research Institute, Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA
4 Pathology Associates International, National Center for Toxicological Research, Jefferson, AR 72079, USA

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


  Abstract

Streptozotocin (STZ)-induced diabetic (DB) mice challenged with single ordinarily lethal doses of acetaminophen (APAP), carbon tetrachloride (CCl4) or bromobenzene (BB) were resistant to all three hepatotoxicants. Mechanisms of protection against APAP hepatotoxicity were investigated. Plasma alanine aminotransferase, aspartate aminotransferase and liver histopathology after APAP administration revealed significantly lower hepatic injury in DB mice. HPLC analysis of plasma and urine levels of APAP and metabolites revealed lower plasma t1/2, increased volume of distribution (Vd) and increased plasma clearance (CLp) of APAP in the DB mice and no difference in APAP-glucuronide, a major metabolite in mice. Interestingly, covalent binding of 14C-labeled APAP to liver target proteins, arylation of APAP to 58, 56 and 44 kDa acetaminophen binding proteins (ABPs) and glutathione (GSH) depletion in the liver did not differ between non-DB and DB mice in spite of down regulated hepatic microsomal CYP2E1 and 1A2 proteins in the DB mice, known to be involved in bioactivation of APAP. Compensatory cell division measured via 3H-thymidine pulse labeling and immunohistochemical staining for proliferating cell nuclear antigen (PCNA) indicated earlier onset of S-phase in the DB mice after exposure to APAP. Antimitotic intervention of liver cell division by colchicine (CLC) after administration of APAP led to significantly higher mortality in the DB mice suggesting a pivotal role of liver cell division and tissue repair in the protection afforded by diabetes. In conclusion, the resistance of DB mice against hepatotoxic and lethal effects of APAP appears to be mediated by a combination of enhanced APAP clearance and robust compensatory tissue repair.

covalent binding, CYP2E1, diabetes, species differences, tissue repair .


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