RT Journal Article
SR Electronic
T1 Potentiation of Carbon Tetrachloride Hepatotoxicity and Lethality in Type 2 Diabetic Rats
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 694
OP 704
DO 10.1124/jpet.103.058834
VO 308
IS 2
A1 Sharmilee P. Sawant
A1 Ankur V. Dnyanmote
A1 Kartik Shankar
A1 Pallavi B. Limaye
A1 John R. Latendresse
A1 Harihara M. Mehendale
YR 2004
UL http://jpet.aspetjournals.org/content/308/2/694.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics