1 Section of Biochemistry and Molecular Biology, Department of Chemistry, Faculty of Medicine, University of Catania, Catania, Italy. 2 Department of Neurochemistry, Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, U.K. 3 Scientific Department, Sigma Tau S.p.A., via Pontina Km 30,400, Pomezia, Rome, Italy. 4 Address reprint requests to: Prof. Vittorio Calabrese, MD, PhD., Section of Biochemistry and Molecular Biology, Faculty of Medi- cine, Department of Chemistry Viale Andrea Doria N o 6, 95100 Catania, Italy. E-mail: calabres@mbox.unict.it Effects of Acetyl-L-Carnitine on the Formation of Fatty Acid Ethyl Esters in Brain and Peripheral Organs after Short-Term Ethanol Administration in Rat V. Calabrese, 1 G. Scapagnini, 1 C. Catalano, 1 F. Dinotta, 1 T. E. Bates, 2 M. Calvani, 3,4 and A. M. Giuffrida Stella 1 (Accepted December 11, 2000) Increasing evidence suggests that Fatty acid ethyl esters (FAEE) play a central role in ethanol in duced organ damage. In the current study we measured FAEE formation in rats after short-term oral administration of ethanol, in the presence and absence of pre-treatment with acetyl-L-carni- tine. Ethanol treatment caused a significant increase in the levels of FAEE, particularly in the br and heart, but also in the kidney and liver. Increases in FAEE were associated with a significant increase in FAEE synthase activity, GSH transferase activity, and lipid hydroperoxide levels. Pre treatment with acetyl-L-carnitine resulted in a significant reduction of FAEE accumulation, de- crease in FAEE synthase and GSH transferase activities, and lipid hydroperoxide levels. Administration of acetyl-L-carnitine greatly reduced the metabolic abnormalities due to non-ox- idative ethanol metabolism, through an increment in lipid metabolism/turnover and by the modu lation of the activities of enzymes associated with FAEE synthesis. These results suggest potentially important pharmacological role for acetyl-L-carnitine in the prevention of alcohol-in- duced cellular damage. KEY WORDS: Ethanol; fatty acid ethyl esters; glutathione S-transferase; fatty acid ethyl ester synthase; oxidative stress; acetyl-L-carnitine. Neurochemical Research, Vol. 26, No. 2, 2001, pp. 167–174 167 0364-3190/01/0200–0167$19.50/0 © 2001 Plenum Publishing Corporation lipids in various cells throughout the body. However, it is not clear whether these alterations are related to any pharmacological effects of ethanol, per se, or to its ox- idative metabolism, which produces oxidants and free radical-mediated reactions. It is generally accepted that acetaldehyde, the end product of ethanol metabolism, contributes to alcohol-induced disease in the liver. However, this oxidative metabolism of ethanol cannot account for cellular damage in organs such as brain, heart or pancreas, as this metabolic pathway is minimal or absent (1) and these tissues are free of substantial ac- etaldehyde production (2). Thus, other biochemical mediators may be important in the pathogenesis of al- cohol-induced organ damage. Recently, a new pathway for alcohol metabolism has been reported (3–4), whose products, fatty acid ethyl esters (FAEE) are actively synthesized from fatty INTRODUCTION Chronic alcoholism is a major public health prob- lem and causes cellular damage to many organs in the human body including the brain. The molecular pathol- ogy of ethanol is almost certainly multi-factorial, but one of its major effects is to alter the composition of