Journal of International Dental and Medical Research ISSN 1309-100X Effect Of L-Citrulline On Doxorubicin-Induced http://www.jidmr.com Samuel Pratama and et al Volume ∙ 12 ∙ Number ∙ 2 ∙ 2019 Page 797 The Effect Of L-Citrulline on Doxorubicin-Induced Cardiotoxicity Using Serum Oxidative Stress Biomarkers Samuel Pratama 1 , Wawaimuli Arozal 2 , Melva Louisa 2 , Vivian Soetikno 2 * 1. Undergraduate student of International Class Program Faculty of Medicine, University of Indonesia, Jakarta, Indonesia. 2. Department of Pharmacology and Therapeutic, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia. Abstract Doxorubicin (DOX) is a chemotherapeutic agent widely used against various cancers. However, its usage is linked to cardiotoxicity side effects via production of reactive oxygen species, causing oxidative stress and cardiac myocyte death. L-Citrulline (CIT) is a potent anti-oxidant agent with potential to prevent DOX-induced cardiotoxicity. This study analyzed the effect of CIT against DOX- induced cardiotoxicity using oxidative stress biomarkers. Administration of DOX (intraperitoneal injection) was performed to induce cardiotoxicity in 20 Wistar rats, divided into 4 groups. Two doses (300 and 600 mg/kg of body weight) of CIT were administered via gavage prior to, during, and after DOX injection. Serum levels of glutathione (GSH) and malondialdehyde (MDA) were measured using colorimetric analysis. Both doses of CIT increase slightly the concentration of GSH (P=.063 vs. control). The concentration of MDA was also increased in the low-dose (P=0.103), and high- dose groups (P<0.001). The observed elevations were dose-dependent. Administration of CIT did not exert a beneficial effect against DOX-induced cardiotoxicity. The increased level of MDA in CIT group indicates increased oxidative stress and lipid peroxidation. Moreover, the elevation of the level of GSH is more likely to be caused by the apoptosis-related GSH efflux mechanism, explained in other literature. Experimental article (J Int Dent Med Res 2019; 12(2): 797-802) Keywords: L-Citrulline, doxorubicin, cardiotoxicity, oxidative stress Received date: 12 February 2019 Accept date: 19 March 2019 Introduction Cancer is a major cause of both morbidity and mortality. In 2015, this disease was responsible for 8.8 million deaths worldwide. 1 There are numerous treatment options available for the treatment of cancer. Frequently, treating physicians administer powerful cytotoxic drugs to suppress the growth of cancerous cells. Consequently, this also affects healthy cells, resulting in the development of adverse effects. Doxorubicin (DOX) is a chemotherapeutic agent widely used against various types of cancer. Its function involves several mechanisms, such as inhibition of topoisomerase II, DNA intercalation, generation of semiquinone free radicals, and iron-dependent production of oxygen free radicals. 2 However, the iron-dependent production of oxygen free radicals has been linked to the development of cardiotoxicity. This cumulative- dose dependent adverse effect greatly limits the usage and safety of DOX as a chemotherapeutic agent. 3 Numerous studies have shown that superoxide produced through the metabolism of DOX reacts with iron to create hydroxyl radicals, leading to damage in various cell compartments and cardiac myocyte death (the iron-reactive oxygen species [ROS] hypothesis). 4 Studies have extensively investigated options for the management or prevention of this adverse effect of DOX. Although various agents (i.e., PEGylated liposomal form, beta-adrenergic blocker carvedilol) and methods (altering the duration of DOX infusion) have been examined, the results have been inconsistent. 5,6 Currently, the only approved drug used to counteract the adverse effects of DOX is the iron chelator dexrazoxane. However, it was revealed that dexrazoxane reduces the efficacy of DOX, induces various adverse effects, and is not cost- effective. 7 Therefore, there is an unmet need for alternative cardioprotective agents to prevent the *Corresponding author: Vivian Soetikno Department of Pharmacology and Therapeutic Faculty of Medicine, Universitas Indonesia Jakarta, Indonesia Email: vivian_09st@yahoo.com; samuel.pratama@gmail.com