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TOXICOLOGY

Potentiation of Carbon Tetrachloride Hepatotoxicity and Lethality in Type 2 Diabetic Rats

Department of Toxicology, School of Pharmacy, University of Louisiana at Monroe, Monroe, Louisiana (S.P.S., A.V.D., K.S., P.B.L., H.M.M.); and Pathology Associates International, National Center for Toxicological Research, Jefferson, Arkansas (J.R.L.)

There is a need for well characterized and economical type 2 diabetic model that mimics the human disease. We have developed a type 2 diabetes rat model that closely resembles the diabetic patients and takes only 24 days to develop robust diabetes. Nonlethal doses of allyl alcohol (35 mg/kg i.p.), CCl₄ (2 ml/kg i.p.), or thioacetamide (300 mg/kg i.p.) yielded 80 to 100% mortality in diabetic rats. The objective of the present study was to investigate two hypotheses: higher CCl₄ bioactivation and/or inhibited compensatory tissue repair were the underlying mechanisms for increased CCl₄ hepatotoxicity in diabetic rats. Diabetes was induced by feeding high fat diet followed by a single dose of streptozotocin on day 14 (45 mg/kg i.p.) and was confirmed on day 24 by hyperglycemia, normoinsulinemia, and oral glucose intolerance. Time course studies (0–96 h) of CCl₄ (2 ml/kg i.p.) indicated that although initial liver injury was the same in nondiabetic and diabetic rats, it progressed only in the latter, culminating in hepatic failure, and death. Hepatomicrosomal CYP2E1 protein and activity, lipid peroxidation, glutathione, and ¹⁴CCl₄ covalent binding to liver tissue were the same in both groups, suggesting that higher bioactivation-based injury is not the mechanism. Inhibited tissue repair resulted in progression of injury and death in diabetic rats, whereas in the nondiabetic rats robust tissue repair resulted in regression of injury and survival after CCl₄ administration. These studies show high sensitivity of type 2 diabetes to model hepatotoxicants and suggest that CCl₄ hepatotoxicity is potentiated due to inhibited tissue repair.

Address correspondence to: Dr. Harihara M. Mehendale, Department of Toxicology, School of Pharmacy, The University of Louisiana at Monroe, 700 University Ave., Monroe, LA 71209-0470. E-mail: mehendale{at}ulm.edu

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