International Journal of Medical, Medicine and Health Sciences ISSN: 2517-9969 Vol:7, No:6, 2013 285 Abstract—The possible therapeutic effect of cannabidiol, the major non-psychotropic Cannabis constituent, was investigated against acute hepatotoxicity induced by a single oral dose of acetaminophen (500mg/kg) in mice. Cannabidiol (two intraperitoneal injections, 5mg/kg, each) was given 1 hour and 12 hours following acetaminophen administration. Acetaminophen administration caused significant elevations of serum alanine aminotransferase, and hepatic malondialdehyde, and nitric oxide levels, and a significant decrease in hepatic reduced glutathione. Cannabidiol significantly attenuated the deterioration in the measured biochemical parameters resulted from acetaminophen administration. Also, histopathological examination showed that cannabidiol markedly attenuated ameliorated acetaminophen-induced liver tissue damage. These results emphasize that cannabidiol represents a potential therapeutic option to protect against acetaminophen hepartotoxicity which is a common clinical problem. Keywords—cannabidiol, acetaminophen, liver, mice. I. INTRODUCTION CETAMINOPHEN (paracetamol) is a commonly used analgesic and antipyretic agent. At therapeutic doses, it is usually safe and well tolerated. However, acute acetaminophen overdose causes severe and fatal hepatotoxicity [1]. A significant amount of acetaminophen is metabolized by the cytochrome P450 system to form the highly reactive intermediate metabolite, N-acetyl-p- benzoquinoneimine which depletes hepatic glutathione and then binds covalently to the intracellular proteins including mitochondrial proteins [2]. The resulting mitochondrial oxidant stress and peroxynitrite formation leads to mitochondrial dysfunction, adenosine triphosphate depletion, increased mitochondrial permeability transition and nuclear DNA fragmentation, which contribute to hepatocellular necrosis. Acetaminophen also activates Kupffer cells which release numerous cytokines and signaling molecules, including nitric oxide and superoxide with increased peroxynitrite formation [3]. Amr A. Fouad is with the Department of Biomedical Sciences, Pharmacology Division, College of Medicine, King Faisal University, Al- Ahsa, Saudi Arabia (Primary affiliation: Department of Pharmacology, Faculty of Medicine, Minia University, El-Minia, Egypt). (Corresponding author to provide phone: +966 501776517; e-mail: amrfouad65@yahoo.com). Waleed H. Albuali is with the Department of Pediatrics, College of Medicine, King Faisal University, Al-Ahsa, Saudi Arabia. Iyad Jresat is with the Department of Biomedical Sciences, Pathology Division, College of Medicine, King Faisal University, Al-Ahsa, Saudi Arabia. Cannabidiol is the major non-psychoactive cannabinoid component derived from the plant Cannabis sativa. It possesses powerful antioxidant and anti-inflammatory activities [4], [5]. However, the exact mechanisms of action of cannabidiol remain obscure. Previous reports proved that cannabidiol may have therapeutic utility in a number of conditions involving inflammation and oxidative stress, including diabetes mellitus, rheumatoid arthritis and neurodegenerative disorders [6]-[8]. However, to the best of our knowledge, the protective effect of cannabidiol against acetaminophen-induced hepatotoxicity was not studied before. II. MATERIALS AND METHODS A. Animals Male Swiss albino mice, weighing 25-30g were obtained from the Animal House, College of Medicine, King Faisal University. The animals were housed at 24±1ºC, 45±5% humidity and 12h light-12h dark cycle. They were supplied with standard laboratory chow and water ad libitum, and left to acclimatize for 1 week before the experiments. The experimental procedures were carried out in accordance with international guidelines for care and use of laboratory animals. B. Drugs and Chemicals Cannabidiol powder (Cayman Chemical Company, USA) was prepared in 1% aqueous solution of Tween 80. Acetaminophen powder (Sigma-Aldrich Co., USA) was prepared in normal saline stabilized by 0.2% gum. The doses of cannabidiol and acetaminophen used in the present work were selected bases on our preliminary experiments and in accordance with previous reports [9], [10]. C. Experimental Design The mice were randomly allocated to three groups (n=8, each). The first group received a single oral dose of normal saline stabilized by 0.2% gum (vehicle of acetaminophen), and served as control group. Hepatotoxicity was induced in mice of the second and third groups by a single oral dose of acetaminophen (500mg/kg). The animals of the second and third groups respectively received two intraperitoneal injections of the vehicle of cannabidiol (1% aqueous solution of Tween 80) or cannabidiol (5mg/kg, each), given 1 and 12 hours following acetaminophen administration. D. Sample Preparation and Biochemical Analysis The mice were euthanized 24 hours following the acetaminophen administration. Blood samples were collected, Amr A. Fouad, Waleed H. Albuali, and Iyad Jresat Cannabidiol Treatment Ameliorates Acetaminophen-Induced Hepatotoxicity in Mice A