doi: 10.1111/j.1472-8206.2009.00810.x ORIGINAL ARTICLE Hepatoprotective, antinociceptive and antioxidant activities of cimetidine, ranitidine and famotidine as histamine H 2 receptor antagonists Amirhossein Ahmadi a , Mohammad Ali Ebrahimzadeh b *, Saeb Ahmad-Ashrafi a , Mohammad Karami b , Mohammad Reza Mahdavi c , Seyed Soheil Saeedi Saravi a a Student Research Committee, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran b Pharmaceutical Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran c Department of Clinical Laboratory, Faculty of Paramedical Sciences, Mazandaran University of Medical Sciences, Sari, Iran INTRODUCTION Histamine H 2 receptor antagonists such as cimetidine, ranitidine and famotidine are widely used for prophylaxis against gastric aspiration syndrome [1]. These drugs are also given to patients undergoing major surgery (e.g., cardiovascular surgery, neurosurgery, organ trans- plantation) to prevent stress ulceration [2]. H 2 blockers competitively inhibit H 2 receptors. Like histamine, cimetidine has an imidazole ring. Ranitidine possesses a Keywords antinociceptive, antioxidant activity, H 2 receptor blockers, hepatoprotective Received 10 August 2009; revised 12 November 2009, 4 December 2009; accepted 18 December 2009 *Correspondence and reprints: zadeh20@yahoo.com ABSTRACT The antioxidant, antinociceptive and hepatoprotective effects of H 2 receptor blockers were examined with different experimental models. Antioxidant activities were deter- mined by employing various in vitro assay systems such as 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical-scavenging activity assays, reducing power determination assays, nitric oxide-scavenging activity assays and hydrogen peroxide-scavenging activity assays. Antinociceptive effects were determined using the hot plate test in mice. The hepatoprotective effects of cimetidine, ranitidine and famotidine against hepatotoxicity induced by carbon tetrachloride (CCl 4 ) were determined by measuring the levels of serum enzymes alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP) activities in mice. We found that the IC 50 values of cimetidine, ranitidine and famotidine on DPPH radical-scavenging activity were 671 ± 28, 538 ± 21 and 955 ± 43 lg/mL, respectively. Famotidine showed very strong nitric oxide-scavenging activity. All three compounds showed very weak hydrogen peroxide-scavenging activity. Moreover, the compounds did not exhibit any reducing power activity until concentrations of 1.6 mg/mL. All compounds also showed a dose-dependent and marked analgesic activity in mice relative to controls. Pretreatment of mice with cimetidine, ranitidine or famotidine for three consecutive days reduced CCl 4 -induced hepatotoxicity in mice. Treatment with 200 mg/kg ranitidine reduced AST, AST and ALP serum levels, while 200 and 40 mg/kg of cimetidine and famotidine, respectively, reduced AST and ALP serum levels. H 2 blockers exhibited varying levels of antioxidant activities in various assays. Our results indicate that the antioxidant activities of H 2 blockers have an analgesic activity and protective effect on CCl 4 -induced hepatotoxicity in mice. These effects were greater with ranitidine than with the other compounds. ª 2010 The Authors Journal compilation ª 2010 Socie ´ te ´ Franc ¸aise de Pharmacologie et de The ´ rapeutique Fundamental & Clinical Pharmacology 1