Potentiation of carbon tetrachloride hepatotoxicity and lethality in type 2 diabetic rats.
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.), CCl(4) (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 CCl(4) bioactivation and/or inhibited compensatory tissue repair were the underlying mechanisms for increased CCl(4) 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 CCl(4) (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 (14)CCl(4) 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 CCl(4) administration. These studies show high sensitivity of type 2 diabetes to model hepatotoxicants and suggest that CCl(4) hepatotoxicity is potentiated due to inhibited tissue repair.
Sawant
Sharmilee P
SP
Department of Toxicology, School of Pharmacy, The University of Louisiana at Monroe, 71209-0470, USA.
Dnyanmote
Ankur V
AV
Shankar
Kartik
K
Limaye
Pallavi B
PB
Latendresse
John R
JR
Mehendale
Harihara M
HM
D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity*; D002252:Carbon Tetrachloride Poisoning; D056486:Chemical and Drug Induced Liver Injury / Q000401:mortality / Q000473:pathology*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D004195:Disease Models, Animal; D005978:Glutathione / Q000378:metabolism; D015227:Lipid Peroxidation / Q000502:physiology; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012680:Sensitivity and Specificity
D018809:Proliferating Cell Nuclear Antigen; D002251:Carbon Tetrachloride; D019392:Cytochrome P-450 CYP2E1; D005978:Glutathione