PMID- 18325728 OWN - NLM STAT- MEDLINE DCOM- 20080725 LR - 20131121 IS - 0887-2333 (Print) IS - 0887-2333 (Linking) VI - 22 IP - 4 DP - 2008 Jun TI - Effect of chronic ethanol exposure on the hepatotoxicity of ecstasy in mice: an ex vivo study. PG - 910-20 LID - 10.1016/j.tiv.2008.01.010 [doi] AB - 3,4-Methylenedioxymethamphetamine (MDMA) is frequently consumed at "rave" parties by polydrug users that usually take this drug in association with ethanol. In addition, many young people are repeatedly exposed to ethanol, which likely leads to tolerance phenomena. Both compounds are metabolized in the liver, with formation of hepatotoxic metabolites, which gives high relevance to the evaluation of their putative toxicological interaction. Therefore, the aim of this study was to evaluate the toxicity induced by 0.8 and 1.6 mM MDMA to freshly isolated hepatocytes obtained from ethanol-treated mice whose tap drinking water was replaced by a 5% ethanol solution for 1 week and, afterwards, by a 12% ethanol solution for 8 weeks (ethanol group) comparatively to non-treated animals (non-ethanol group). The hepatocytes were incubated under normothermic and hyperthermic conditions in order to simulate in vitro the hyperthermic response induced in vivo by MDMA, a condition that has been recognized as a life-threatening effect associated with MDMA exposure and implicated in its hepatotoxicity. Six mice treated under the same protocol as the ethanol group were used for histological analysis, and compared to non-ethanol-treated animals. The pre-treatment of mice with ethanol caused a significant decrease in the hepatocytes yield in the isolation procedure comparatively to the non-ethanol group, which can be explained by an increase in collagen deposition along the hepatic parenchyma as observed in the histological analysis. The initial cell viability of hepatocytes suspensions was similar between ethanol and non-ethanol groups. However, the ethanol group showed a higher GSH oxidation rate, which was enhanced under hyperthermia. Additionally, a concentration-dependent MDMA-induced loss of cell viability and ATP depletion was observed for both groups, at 41 degrees C. In conclusion, the repeated treatment with ethanol seems to increase the vulnerability of freshly isolated mice hepatocytes towards pro-oxidant conditions, as ascertained by the increase in collagen deposition, lower hepatocyte yield and decreased glutathione levels. However, MDMA toxicity to the isolated hepatocytes was independent of ethanol pre-treatment, while significantly dependent on incubation temperature. FAU - Pontes, Helena AU - Pontes H AD - REQUIMTE, Toxicology Department, Faculty of Pharmacy, University of Porto, Rua Anibal Cunha 164, 4099-030 Porto, Portugal. hpontes@ff.up.pt FAU - Santos-Marques, Maria Joao AU - Santos-Marques MJ FAU - Fernandes, Eduarda AU - Fernandes E FAU - Duarte, Jose Alberto AU - Duarte JA FAU - Remiao, Fernando AU - Remiao F FAU - Carvalho, Felix AU - Carvalho F FAU - Bastos, Maria Lourdes AU - Bastos ML LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20080126 PL - England TA - Toxicol In Vitro JT - Toxicology in vitro : an international journal published in association with BIBRA JID - 8712158 RN - 3K9958V90M (Ethanol) RN - 8L70Q75FXE (Adenosine Triphosphate) RN - 9007-34-5 (Collagen) RN - GAN16C9B8O (Glutathione) RN - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine) SB - IM MH - Adenosine Triphosphate/metabolism MH - Alcohol Drinking/*adverse effects MH - Animals MH - Cell Survival/drug effects MH - Collagen/drug effects/metabolism MH - Dose-Response Relationship, Drug MH - Drug Interactions MH - Ethanol/*toxicity MH - Fever/metabolism MH - Glutathione/drug effects/metabolism MH - Hepatocytes/*drug effects/metabolism MH - Liver/cytology/drug effects/pathology MH - Male MH - Mice MH - N-Methyl-3,4-methylenedioxyamphetamine/administration & dosage/*toxicity MH - Oxidation-Reduction/drug effects MH - Temperature EDAT- 2008/03/08 09:00 MHDA- 2008/07/26 09:00 CRDT- 2008/03/08 09:00 PHST- 2007/10/19 00:00 [received] PHST- 2007/12/17 00:00 [revised] PHST- 2008/01/14 00:00 [accepted] PHST- 2008/03/08 09:00 [pubmed] PHST- 2008/07/26 09:00 [medline] PHST- 2008/03/08 09:00 [entrez] AID - S0887-2333(08)00026-X [pii] AID - 10.1016/j.tiv.2008.01.010 [doi] PST - ppublish SO - Toxicol In Vitro. 2008 Jun;22(4):910-20. doi: 10.1016/j.tiv.2008.01.010. Epub 2008 Jan 26.