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Effects of Histidine and N-Acetylcysteine on Doxorubicin-InducedCardiomyopathy in RatsAmir Abbas Farshid • Esmaeal Tamaddonfard •Naeime Simaee • Sanam Mansouri •Sima Najaf i• Siamak Asri-Rezaee • Hossein AlaviPublished online: 17 December 2013? Springer Science+Business Media New York 2013Abstract The amino acids histidine and n-acetylcysteinehave many biological activities such as antioxidant effect.The present study investigated the effects of histidine andn-acetylcysteine on the heart lesions induced by doxoru-bicin (DOX) in rats. Forty-eight male Wistar rats weredivided into two major groups treated intraperitoneally(i.p.) with normal saline and 4 mg/kg of DOX, respec-tively. Each group was further divided into four subgroupsthat were treated with separate and combined i.p. injectionsof histidine and n-acetylcysteine (NAC) at a same dose of40 mg/kg. Electrocardiography (ECG) was recorded usinglead II. The heart lesions were evaluated by light micros-copy. Serum levels of creatine phosphokinase and lactatedehydrogenase and heart tissue malondialdehyde levelswere measured. Histidine and especially NAC at a samedose of 40 mg/kg recovered ECG changes, improved heartlesions and prevented biochemical changes induced byDOX. Co-administration of histidine and NAC showedbetter responses when compared with them used alone. Theresults of the present study showed protective effects forhistidine and NAC on the heart. Reduction in free radical-induced toxic effects may be involved in cardioprotectiveproperties of histidine and NAC.Keywords Doxorubicin ? ECG ? Heart ? Histidine ?N-acetylcysteine ? RatsIntroductionDoxorubicin (DOX) is a highly effective chemotherapeuticagent used in the treatment for solid and hematopoietictumors, including breast cancer, leukemia and sarcomas[1]. Although DOX has been shown to be effective, itsclinical use is limited due to its dose-dependent cardio-toxicity [2]. Several mechanisms including free radicalproduction, calcium overloading and mitochondrial dys-function have been proposed for DOX-induced cardiotox-icity [3, 4]. Chemopreventive agents including vitamin E (apotent antioxidant), carvedilol (a beta-adrenergic blocker),dexrazoxane (an iron-chelating agent) and enalapril (anangiotensin-converting enzyme inhibitor) have been usedfor reducing the side effects of DOX on the heart [5].The preventive effects of amino acids such as taurineand glutamine have reported on DOX-induced adversetoxic effects on the heart [6, 7]. Histidine, as a semi-essential amino acid, has many biological functionsincluding anti-inf l ammatory, antiedematous, analgesic andantioxidant activities [8–13]. A cardioprotective effect hasbeen explained for histidine [14]. n-Acetylcysteine (NAC),the acetylated variant of the amino acid L -cysteine, isconverted in the body into metabolites capable of stimu-lating glutathione synthesis, promoting detoxif i cation andacting directly as free radical scavengers [15]. Pretreatmentwith NAC reduced DOX-induced cardiotoxicity in miceand rats [16, 17].A. A. Farshid (&)Department of Pathobiology, Faculty of Veterinary Medicine,Urmia University, 57153-1177 Urmia, Irane-mail: amirabbasfarshidkh@gmail.com; aa.farshid@urmia.ac.irE. TamaddonfardDepartment of Basic Sciences, Faculty of Veterinary Medicine,Urmia University, 57153-1177 Urmia, IranN. Simaee ? S. Mansouri ? S. Najaf i ? H. AlaviFaculty of Veterinary Medicine, Urmia University,57153-1177 Urmia, IranS. Asri-RezaeeDepartment of Clinical Sciences, Faculty of VeterinaryMedicine, Urmia University, 57153-1177 Urmia, Iran123Cardiovasc Toxicol (2014) 14:153–161DOI 10.1007/s12012-013-9239-6