Protective effect of type 2 diabetes on acetaminophen-induced hepatotoxicity in male Swiss-Webster mice.
Type 2 diabetic (DB) mice exposed to CCl(4) (LD(50) = 1.25 ml/kg), acetaminophen (LD(80) = 600 mg/kg; APAP), and bromobenzene (LD(80) = 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 [(14)C]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.
Sawant
Sharmilee P
SP
Department of Toxicology, College of Pharmacy, University of Louisiana at Monroe, Monroe, 71209-0470, USA.
Dnyanmote
Ankur V
AV
Mitra
Mayurranjan S
MS
Chilakapati
Jaya
J
Warbritton
Alan
A
Latendresse
John R
JR
Mehendale
Harihara M
HM
D000082:Acetaminophen / Q000009:adverse effects* / Q000493:pharmacokinetics; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects* / Q000493:pharmacokinetics; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology* / Q000473:pathology; D004790:Enzyme Induction; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains
D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen; D019392:Cytochrome P-450 CYP2E1; D005978:Glutathione