title: The effect of glucagon and cyclic adenosine monophosphate on acute liver damage induced by acetaminophen.
abstract: Recent investigations suggest that glucagon might have a potentially important hepatoprotective activity. We investigated the effect of glucagon in a model of acetaminophen-induced liver injury. CBA male mice were injected intraperitoneally with a lethal (300 mg/kg) or sublethal (150 mg/kg) dose of acetaminophen. The liver injury was assessed by observing the survival of mice, by liver histology and by measuring the concentration of alanine-aminotransferase (ALT). Inducible nitric oxide synthase (iNOS) and nuclear factor kappa B (NF-κB) protein expressions were determined immunohistochemically. Hepatic levels of reduced glutathione (GSH) and cyclic adenosine monophosphate (cAMP) were also measured. Results show that glucagon, dose and time dependently, protects against acetaminophen-induced hepatotoxicity. This protection was achieved with a dose of 0.5 mg/kg of glucagon given intraperitoneally 15 min before or 1 h after acetaminophen. Treatment of animals with acetaminophen elevated ALT and nitrite/nitrate concentration in the plasma, enhanced iNOS and NF-κB expression and reduced GSH and cAMP concentration in the liver. Animals treated with glucagon had higher hepatic cAMP level, lower ALT and nitrite/nitrate concentration in plasma and lower expression of iNOS in liver cells than animals in control group, whereas there was no difference in the expression of NF-κB. Glucagon did not prevent the loss of GSH content caused by acetaminophen. Our investigation indicates that glucagon has a moderately protective effect against acetaminophen-induced liver injury, which is, at least partially, mediated through the downregulation of iNOS and through the increase in hepatic cAMP content, but it is not mediated through the modulation of NF-κB activity.
authors.affiliation: Department of Physiology, School of Medicine, University of Zagreb, Croatia. tkelava@mef.hr
authors.forename: Tomislav
authors.initials: T
authors.lastname: Kelava
authors.forename: Ivan
authors.initials: I
authors.lastname: Ćavar
authors.forename: Katarina
authors.initials: K
authors.lastname: Vukojevic
authors.forename: Mirna
authors.initials: M
authors.lastname: Saraga-Babic
authors.forename: Filip
authors.initials: F
authors.lastname: Culo
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects*; D000208:Acute Disease; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000473:pathology*; D000242:Cyclic AMP / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005934:Glucagon / Q000008:administration & dosage / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008099:Liver / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D000082:Acetaminophen; D005934:Glucagon; D000242:Cyclic AMP; D052247:Nitric Oxide Synthase Type II; D000410:Alanine Transaminase; D005978:Glutathione