Life Sciences, Vol. 66, No. 26, pp. 2583-2591 2000 Copyright 0 2000 zyxwvutsrqponmlkjih Elsevier ScienceInc. Printed in the USA. Ail rights reserved 0024-3205/00/S-see tiunt matter ELSEVIER PII zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFED SO0243205(00)00592-O PROTECTIVE EFFECTS OF THYMOQUINONE AND DESFERRIOXAMINE AGAINST HEPATOTOXICITY OF CARBON TETRACHLORIBE IN MICE Mahmoud A. Mansour Department of Pharmacology, College of Pharmacy, King Saud University, P.0 Box 2457, Riyadh 11451, Saudi Arabia. (Received in final form February 1,2OOO) Summary The effects of thymoquinone (TQ) and desferrioxamine (DFO) against carbon tetrachloride (CC&)-induced hepatotoxicity were investigated. A single dose of CC14 (20 ul/kg, i.p.) induced hepatotoxicity, manifested biochemically by significant elevation of activities of serum enzymes, such as alanine transaminase (ALT, EC: 2.6.1.2 ) , aspartate transaminase (AST, EC: 2.6.1.1 ) and lactate dehydrogenase (LDH, EC: 1.1.1.27). Hepatotoxicity was further evidenced by significant decrease of total sulfhydryl (-SH) content, and catalase (BC: 1.11.1.6) activity in hepatic tissues and significant increase in hepatic lipid peroxidation measured as malondialdhyde (MDA). Pretreatment of mice with DFO (200 mg/kg i.p.) 1 h before CC4 injection or administration of TQ (16 mg/kdday, p.o.) in drinking water, starting 5 days before CCll injection and continuing during the experimental period, ameliorated the hepatotoxicity induced by CC&, as evidenced by a significant reduction in the elevated levels of serum enzymes as well as a significant decrease in the hepatic MDA content and a significant increase in the total sulthydryl content 24 h after CCL administration. In a separate in vitro assay, TQ and DFO inhibited the non-enzymatic lipid peroxidation of normal mice liver homogenate induced by Fe3+/ascorbate in a dose-dependent manner. These results indicate that TQ and DFO are efficient cytoprotective agents against CC&-induced hepotoxicity, possibly through inhibition of the production of oxygen free radicals that cause lipid peroxidation. Key Wwds: thymoquinone, desferrioxamine, carbon tetrachloride, hepatotoxicity Carbon tetrachloride (CC14)is a xenobiotic which produces hepatotoxicity in humans as well as in animals (1,2). The hepatotoxic effect of CC4 is thought to result from its reductive dehalogenation by the P-450 enzyme system to the highly reactive free radical, trichloromethyl radical ‘CC13(3). This radical quickly adds molecular oxygen to form trichloromethylperoxy radical (4). Removal of hydrogen atoms from unsaturated fatty acids by such radical created carbon-centered lipid radicals (3). These lipid radicals quickly add molecular oxygen to form lipid peroxyl radicals, thereby, initiating the process of lipid peroxidation. Unless scavenged by radical scavengers, these lipid peroxyl radicals in turn abstract hydrogen atoms from other lipids molecules, thereby propagating the process of lipid peroxidation (5). Iron can catalyze oxygen free radical reactions that lead to peroxidation of membrane lipids or inactivation of antioxidant enzyme activities (6), and consequently damage of microsomes, mitochondria, nuclei that lead to imparied physiological functions of hepatocytes (7). Also it has been reported that iron play a role as a mediator of CCLhepatotoxicity (8).