Z ooo be ,'4--', o.- ! t',,,,,,.,; ,,,1>,. ........ _ 4//,.,_,h_, ,,.,,.,,,.,; _ _[iver Ecstasy-induced toxicity in rat liver Beitia G, Cobreros A. Sainz L, Cenarruzabeitia E. Ecstasy-induced toxic- G. Beitia, A. Cobreros,L. Sainzand ity in rat liver. E. Cenarruzabeitia Liver 2000: 20: 8-15. C: Munksgaard, 2(/00 Department of Pharmacology, University of Navarra. 31008 Pamplona, Spain Abstract: BackgroundAims." The aim of the present study was to examine the effects of single and repeated administration of 3.4-methylenedioxyme- thamphetamine (MDMA, "ecstasy") on rat liver. Mefllods." Animals were given an acute (20 mg/kg) and repeated (20 mg/kg, b.i.d., for 4 consecu- tive day's) intraperitoneal dose of MDMA. and at various times after ad- ministration the hepatic and serum determinations were made. Resuhs. The effect of acute MDMA administration included increased triglyceride and cholesterol levels and an increase in all enzyme activities 6 h post adminis- tration. The toxic effect of MDMA was also observed in other hepatic processes. Gly'cogen content showed a marked decrease, which was ac- companied by' a decrease in serum glucose levels. No significant changes in lipid peroxidation and hepatic GSH content were observed. In con- Key words: 3,4-methylenedioxymethampheta- trast, multiple MDMA administration produced some evidence of oxida- mine (MDMA)- liver - lipid per0xidation - tive stress, namely, increased MDA content and decreased GSH content, a reducedglutathi0ne (GSH)- glycogen small decrease in liver glycogen at 3 h recovering 6 h post dose. no effect Dr. E.Cenarruzabeitia. University of Navarra, on blood glucose and increased AST and ALP activities but no effects SchoolofPharmacy, c/Irunlarrea 1, ' on ALl" activity. Seven days after the last MDMA injection a tendency 31008Pamplona, Spain towards recovery was shown. Com'lusiom Our results show that the liver Received 23October1998.acceptedfor . toxicity' caused by' MDMA administration involves several mechanisms, publication 5 August1999 3,4-methylenedioxymethamphetamine (MDMA) opsy, which varied from foci of individual cell ne- commonly' known as "ecstasy" is a synthetic am- crosis to centrilobular necrosis, hepatitis and ex- phetamine derivative that rapidly became a widely tensive fibrosis (1 1-13). The principal evidence of abused drug (1). Patented in 1914 by the E. Merck hepatic lesions, resulting from MDMA in humans, Company as an appetite suppressant, it was never is an unexplained jaundice or hepatomegaly (14, marketed, but in the 1970s and early 1980s the 15). Acute hepatitis has also been associated with drug gained popularity as an adjunct to psycho- repeated use of ecstasy (16, 17). therapy (2). Since MDMA's classification in 1985 The aim of the present study was to obtain evi- as a Schedule I drug under the Controlled Sub- dence for the mechanism involved in MDMA-in- stances Act (3), there has been an increase in clan- duced hepatotoxicity in rats. For this purpose, sev- destine synthesis and illicit use which has been ac- eral parameters of rat liver function were deter- companied by an equivalent increase in the num- mined. ber of MDMA toxicity reports. MDMA intoxication is predominantly associated with the Materials and methods ability of the drug to destroy serotonergic nerve Drugs used terminals (4-7), but there are some reported cases of severe toxicity resulting from recreational mis- The MDMA was obtained from the Audiencia use of small amounts of MDMA in which the pat- Provincial de Navarra. All other reagents were of tern of toxicity included cardiac arrhythmias, the highest grade commercially available and were fulminate hyperthermia, convulsions, disseminated obtained from E. Merck (Darmstadt, Germany) intravascular coagulation, rhabdomyolysis, and and Sigma Chemical Company (St. Louis, MO, acute renal failure (8-10). Hepatotoxicity effects U.S.A.). Catalase, glutathione reductase, glutathi- have only recently been noted. However, there is one peroxidase, glutathione-S-transferase and su- increasing evidence that "ecstasy" is hepatotoxic, peroxide dismutase were purchased from Randox and liver changes have been reported following bi- Laboratories Ltd. (Crumlin, UK). 8