Type 1 Diabetic Mice Are Protected from Acetaminophen Hepatotoxicity
作者： Kartik Shankar , Vishal S Vaidya , Udayan M Apte , Jose E Manautou , Martin JJ Ronis
关键词: Liver cell 、 CYP2E1 、 Carbon tetrachloride 、 Acetaminophen 、 Cytochrome P450 、 Streptozotocin 、 Endocrinology 、 Glutathione 、 Internal medicine 、 Chemistry 、 Toxicity
摘要: Streptozotocin (STZ)-induced diabetic (DB) mice challenged with single ordinarily lethal doses of acetaminophen (APAP), carbon tetrachloride (CCl 4 ), or bromobenzene (BB) were resistant to all three hepatotoxicants. Mechanisms protection against APAP hepatotoxicity investigated. Plasma alanine aminotransferase, aspartate and liver histopathology revealed significantly lower hepatic injury in DB after administration. HPLC analysis plasma urine t 1/2 , increased volume distribution (V d clearance (CL p ) the no difference APAP-glucuronide, a major metabolite mice. Interestingly, covalent binding 14 C-labeled target proteins; arylation 58, 56, 44 kDa proteins (ABPs); glutathione (GSH) depletion did not differ between nondiabetic (non-DB) spite downregulated microsomal CYP2E1 1A2 mice, known be involved bioactivation APAP. Compensatory cell division measured via 3 H-thymidine pulse labeling immunohistochemical staining for proliferating nuclear antigen (PCNA) indicated earlier onset S-phase exposure Antimitotic intervention by colchicine (CLC) administration led higher mortality suggesting pivotal role tissue repair afforded diabetes. In conclusion, resistance hepatotoxic effects appears mediated combination enhanced robust compensatory repair.
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