Streptozotocin-induced diabetic mice are resistant to lethal effects of thioacetamide hepatotoxicity.
The effect of Type 1 diabetes on the toxicity of thioacetamide was investigated in a murine model. In streptozotocin-induced diabetic C57BL6 mice a LD90 dose of thioacetamide (1000 mg/kg, ip in saline) caused only 10% mortality. Alanine aminotransferase activity revealed approximately 2.7-fold less liver injury in the diabetic (DB) mice compared to the non-DB controls, at 36 h after thioacetamide (TA) administration, which was confirmed via histopathological analysis. HPLC analyses revealed lower plasma t(1/2) of TA in the DB mice. Covalent binding of [(14)C]TA to liver tissue was lower in the DB mice, suggesting lower bioactivation of TA. Compensatory hepatic S-phase stimulation as assessed by [(3)H]thymidine incorporation occurred much earlier and was substantially higher in the DB mice compared to the non-DB cohorts. Morphometric analysis of cells in various phases of cell division assessed via immunohistochemical staining for proliferating cell nuclear antigen revealed more cells in G(1), S, G(2), and M phases in the DB mice, indicating robust tissue repair in concordance with the findings of [(3)H]thymidine pulse labeling studies. The importance of tissue repair in the resistance of DB mice was further investigated by blocking cell division in the DB mice by colchicine (1 mg/kg, ip) at 40 h after TA administration, well after the bioactivation of TA. Antimitotic action of colchicine, confirmed by decreased S-phase stimulation, led to progression of liver injury and increased mortality in DB mice. These findings suggest that lower bioactivation of TA and early onset of liver tissue repair are the pivotal underpinnings for the resistance of DB mice.
Shankar
Kartik
K
Department of Toxicology, College of Pharmacy, University of Louisiana at Monroe, LA 71209, USA.
Vaidya
Vishal S
VS
Wang
Tao
T
Bucci
Thomas J
TJ
Mehendale
Harihara M
HM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D003078:Colchicine / Q000494:pharmacology; D004247:DNA / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004798:Enzymes / Q000097:blood; D007150:Immunohistochemistry; D008112:Liver Glycogen / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018809:Proliferating Cell Nuclear Antigen / Q000097:blood; D013853:Thioacetamide / Q000633:toxicity*
D000970:Antineoplastic Agents; D001786:Blood Glucose; D002273:Carcinogens; D004798:Enzymes; D008112:Liver Glycogen; D018809:Proliferating Cell Nuclear Antigen; D013853:Thioacetamide; D004247:DNA; D003078:Colchicine