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TOXICOLOGY

Protective Effect of Type 2 Diabetes on Acetaminophen-Induced Hepatotoxicity in Male Swiss-Webster Mice

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

Type 2 diabetic (DB) mice exposed to CCl₄ (LD₅₀ = 1.25 ml/kg), acetaminophen (LD₈₀ = 600 mg/kg; APAP), and bromobenzene (LD₈₀ = 0.5 ml/kg) i.p. yielded 30, 20, and 20% mortality, respectively, indicating hepatotoxic resistance. Male Swiss-Webster mice were made diabetic by feeding high fat and administrating streptozotocin (120 mg/kg i.p.) on day 60. On day 71, time-course studies after APAP (600 mg/kg) treatment revealed identical initial liver injury in non-DB and DB mice, which progressed only in non-DB mice, resulting in 80% mortality. The hypothesis that decreased APAP bioactivation, altered toxicokinetics, and/or increased tissue repair are the underlying mechanisms was investigated. High-performance liquid chromatography analysis revealed no difference in plasma and urinary APAP or detoxification of APAP via glucuronidation between DB and non-DB mice. Hepatic CYP2E1 protein and activity, glutathione, and [¹⁴C]APAP covalent binding did not differ between DB and non-DB mice, suggesting that lower bioactivation-based injury is not the mechanism of decreased hepatotoxicity in DB mice. Diabetes increased cells in S phase by 8-fold in normally quiescent liver of these mice. Immunohistochemistry revealed overexpression of calpastatin in the newly dividing/divided cells, explaining inhibition of hydrolytic enzyme calpain in perinecrotic areas and lower progression of APAP-initiated injury in the DB mice. Antimitotic intervention of diabetes-associated cell division with colchicine before APAP administration resulted in 70% mortality in APAP-treated colchicine-intervened DB mice. These studies suggest that advancement of cells in the cell division cycle and higher tissue repair protect DB mice by preventing progression of APAP-initiated liver injury that normally leads to mortality.

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

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