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

Abstract

Type 2 diabetic (DB) mice exposed to CCl 4 (LD 50 ϭ 1.25 ml/kg), acetaminophen (LD 80 ϭ 600 mg/kg; APAP), and bromobenzene (LD 80 ϭ 0.5 ml/kg) i.p. yielded 30, 20, and 20% mortality, respectively, indicating hepatotoxic resistance. Male SwissWebster 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 APAPtreated 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.

Differences in Early Acetaminophen Hepatotoxicity between Obeseob/obanddb/dbMice

“…However, these investigations have shown conflicting results. Indeed, whereas some studies showed increased hepatotoxicity (Corcoran and Wong, 1987;Kon et al, 2010;Kučera et al, 2012), others demonstrated no difference or an obvious protection (Blouin et al, 1987;Ito et al, 2006;Sawant et al, 2006). Although the exact reasons for this discrepancy are currently unknown, several hypotheses can be put forward.…”

Diabetes and hypertriglyceridemia modify the mode of acetaminophen-induced hepatotoxicity and nephrotoxicity in rats and mice

“…In this connection, in type 2 diabetic patients, contradictory evidence of increased CPY2E1 (Wang et al, 2003) and unchanged CYP2E1 protein and activity has been reported. Collectively, Sawant et al (2006) suggest are unlikely to explain diabetes-induced protection from APAP-induced hepatotoxicity.…”

“…In STZ-induced type 1 diabetic rats, liver microsomal CYP2E1 protein expression and enzyme activity are markedly increased (Sakuma et al, 2001;Wang et al, 2000), whereas in type 1 diabetic (Sakuma et al, 2001;Shankar et al, 2003a). In type 2 diabetic rats (Sawant et al, 2004) and mice (Sawant et al, 2006) including type 2 ob/ob mice and Zucker rats (Novak and Woodcroft, 2000), CYP2E1 protein and mRNA are not significantly changed. In this connection, in type 2 diabetic patients, contradictory evidence of increased CPY2E1 (Wang et al, 2003) and unchanged CYP2E1 protein and activity has been reported.…”

“…It has generally been reported that diabetes protects rats and mice from APAP-induced hepatotoxicity (Price and Jollow, 1982;Gaynes and Watkins, 1989;Jeffery et al, 1991;Sawant et al, 2006). Price and Jollow (1982) reported that hepatoprotection in insulin-deficient diabetic male rats are due to increased capacity to eliminate the drug as nontoxic glucuronide and sulfate conjugates -ty.…”

“…It is also said that hepatoprotection in type 1 diabetic mice is dependent on peroxisome proliferet al, 2002). Recently, Sawant et al (2006) reported that GSH conjugation may not be underlying mechanisms of the hepatoprotective effects in type 2 diabetic mice since type 2 diabetes does not change GSH status of the liver.…”