Metabolic interactions between ethanol and MDMA in primary cultured rat hepatocytes

• Published in: Toxicology (Amsterdam) 2010-04, Vol.270 (2), p.150-157
• Main Authors: Pontes, Helena, de Pinho, Paula Guedes, Fernandes, Eduarda, Branco, Paula Sério, Ferreira, Luísa Maria, Carmo, Helena, Remião, Fernando, Carvalho, Félix, Bastos, Maria Lourdes
• Format: Article
• Language: English
• Subjects: 3,4-Methylenedioxymethamphetamine; Alcoholism and acute alcohol poisoning; Animals; Biological and medical sciences; Biotransformation; Cell Death - drug effects; Cell Separation; Cells, Cultured; Central Nervous System Depressants - metabolism; Central Nervous System Depressants - toxicity; Cytochrome P-450 CYP2E1 - metabolism; Cytochrome P-450 CYP3A - metabolism; Cytochrome P450; Drug Interactions; Emergency; Ethanol; Ethanol - metabolism; Ethanol - toxicity; Gas Chromatography-Mass Spectrometry; Hallucinogens - metabolism; Hallucinogens - toxicity; Hepatocytes - drug effects; Hepatocytes - enzymology; Hepatocytes - metabolism; L-Lactate Dehydrogenase - metabolism; Male; Medical sciences; Metabolic interactions; N-Methyl-3,4-methylenedioxyamphetamine - metabolism; N-Methyl-3,4-methylenedioxyamphetamine - toxicity; Oxidation-Reduction; Primary cultured rat hepatocytes; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA - biosynthesis; RNA - isolation & purification; Toxicology
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2010.02.010

Abstract 3,4-Methylenedioxymethamphetamine (MDMA; ecstasy), a drug of abuse commonly consumed at rave parties, is often taken in a polydrug abuse scenario, ethanol being one of the most associated drugs. Both MDMA and ethanol are mainly metabolized in the liver with formation of toxic metabolites. Our working hypothesis is that ethanol can modify the metabolism of MDMA through the cytochrome P450 system, and that this effect may be further potentiated by hyperthermia, a well-known consequence of MDMA abuse. To investigate these putative interactions we used primary rat hepatocyte cultures, which were exposed to 300 mM ethanol, 1.6 mM MDMA and the combination of both, at normothermic (36.5 °C) and hyperthermic (40.5 °C) conditions. After 24 h, the levels of MDA, HMA and HMMA in the cell culture medium were quantified by GC/MS. In addition, we repeated the same experimental design preceded by 1 h incubation with 0.18 μM ketoconazole or 150 μM diallyl sulphide (CYP3A and CYP2E1 inhibitors, respectively), to evaluate the putative role of these isoenzymes in the observed effects. The results obtained showed that ethanol exposure increases the formation of some MDMA metabolites such as HMA (1.8 times increase) and MDA (1.5 times increase). This effect was markedly increased under hyperthermic conditions (HMA, MDA and HMMA formation increased 10, 6 and 16 times, respectively) and is mediated, at least partially, by CYP3A and CYP2E1.