1 DrugRes/2014-01-0561/26.2.2014/MPS Original Article DrugRes/2014-01-0561/26.2.2014/MPS Shokrzadeh M et al. Hepatoprotective Eﬀect of Zataria … Drug Res 2014; 64: 1–7 ■ Proof copy for correction only. All forms of publication, duplication or distribution prohibited under copyright law. ■ received 18.01.2014 accepted 10.02.2014 Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1370932 Drug Res 2014; 64: 1–7 © Georg Thieme Verlag KG Stuttgart · New York ISSN 2194-9379 Correspondence A. Ahmadi S. Assadpour Pharmaceutical Sciences Research Center Faculty of Pharmacy Mazandaran University of Medical Sciences 18 kilometer of Farah Abad Road Sari P. Box: 48175-861 Iran Tel.: + 98/151/3543 084 Fax: + 98/151/3543 084 Amirhossein_pharma@yahoo. com SaraAssadpour@yahoo.com Key words ● ▶ hepatoprotective ● ▶ zataria multiﬂora ● ▶ cyclophosphamide ● ▶ liver toxicity ● ▶ antioxidant activity Hepatoprotective Eﬀects of Zataria Multiﬂora Ethanolic Extract on Liver Toxicity Induced by Cyclophosphamide in Mice peroxide (H 2 O 2 ) during its oxidative metabolism, and depresses the antioxidant defense mecha- nisms in the liver [4, 5]. Regarding the above changes in the cells induced by CP, it is signiﬁcant to ﬁnd a compound capable of protecting the healthy cells and tissues against the activity of CP metabolites such as acrolein and free radicals. Various studies show that anti- oxidant intake can control the reaction to chemo- therapy and also minimize the adverse side-eﬀects of antineoplastic drugs [6]. Medici- nal plants have the potential chemopreventive properties because of chemical constituents such as phenolic compounds and ﬂavonoids. The bio- logical beneﬁts of these compounds are generally thought to be a result of their antioxidant and free-radical scavenging properties [7, 8]. Zataria multiﬂora is a potential medicinal plant owned by the Lamiaceae family that is grown extensively in Iran, Pakistan, and Afghanistan. It is greatly used for medicinal and condimental Introduction ▼ Cyclophosphamide (CP), an oxazophosphorine derivative of the classical alkylating agent nitro- gen mustard, is commonly used in cancer chem- otherapy. This drug also has signiﬁcant immunosuppressive activity and is used clini- cally in the treatment of autoimmune diseases and for renal and bone marrow transplantations [1]. However, despite its wide spectrum of clini- cal uses, CP also possesses a wide spectrum of adverse eﬀects including hepatotoxicity in humans and experimental animals [2, 3]. The precise mechanism by which CP causes hepatic injury is poorly understood. However, CP requires metabolic activation by hepatic microsomal cytochrome P450 mixed function oxidase system for both its therapeutic action and its toxicologic actions [1]. Recent studies suggest that CP gener- ates reactive oxygen species (ROS) like superox- ide anion, hydroxyl radical and hydrogen Authors M. Shokrzadeh 1, 2 , A. Chabra 3 , A. Ahmadi 1 , F. Naghshvar 4 , E. Habibi 5 , F. Salehi 4 , S. Assadpour 1 Aﬃliations 1 Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran 2 Department of Toxicology and Pharmacology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran 3 Student Research Committee, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran 4 Department of Pathology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran 5 Department of Pharmacognosy, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran Abstract ▼ ■■■: Although cyclophosphamide (CP), an alkylating agent, has been extensively used in chemotherapy, it possesses a wide spectrum of adverse eﬀects including hepatotoxicity. This study was aimed to evaluate the protective eﬀects of Zataria multiﬂora against hepatic dam- age induced by CP in mice. Methods: Mice were orally (gavages) pre- treated with the ethanolic extract aerial parts of Zataria at doses of 50, 100, 200, or 400 mg/kg for 7 consecutive days before a single intraperitoneal injection of 200 mg/kg CP. After 24 h, animals were anesthetized, blood samples and hepatic tissues were collected and used for biochemical and histological examination. Findings: Serum levels of hepatic markers were signiﬁcantly increased after only CP treated ani- mals but restored in Zataria pretreated groups. A single dose of CP administration also markedly induced abnormality in the levels of several biomarkers associated with oxidative stress in liver tissues homogenates. However, pretreat- ment with Zataria signiﬁcantly inhibited the abnormality of antioxidant enzymes defense sys- tem in the liver tissues. In addition, histopatho- logical studies proved that CP causes damage to the liver, and this was evidenced by the induced dilated and congested sinusoidal space, lym- phocytic inﬁltration between hepatocytes, portal space with moderate to severe inﬂammation and necrotic hepatocyte with absence of nuclei. Zataria eﬀectively protected animals against CP- induced hepatic tissue damages. Conclusions: Our results reveal that Zataria produces a potent hepatoprotective role and could be a potent candidate to use concomitantly as a supplement agent against hepatotoxicity of CP for the patients undergoing chemotherapy.