Metabolic interactions between ethanol and MDMA in primary cultured rat hepatocytes.
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 degrees C) and hyperthermic (40.5 degrees 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 1h incubation with 0.18 microM ketoconazole or 150 microM 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.
Pontes
Helena
H
REQUIMTE, Toxicology Department, Faculty of Pharmacy, University of Porto, Rua Aníbal Cunha 164, 4099-030 Porto, Portugal. hpontes@ff.up.pt
de Pinho
Paula Guedes
PG
Fernandes
Eduarda
E
Branco
Paula Sério
PS
Ferreira
Luísa Maria
LM
Carmo
Helena
H
Remião
Fernando
F
Carvalho
Félix
F
Bastos
Maria Lourdes
ML
D000818:Animals; D001711:Biotransformation; D016923:Cell Death / Q000187:drug effects; D002469:Cell Separation; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000378:metabolism* / Q000633:toxicity*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004347:Drug Interactions; D000431:Ethanol / Q000378:metabolism* / Q000633:toxicity*; D008401:Gas Chromatography-Mass Spectrometry; D006213:Hallucinogens / Q000378:metabolism* / Q000633:toxicity*; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000378:metabolism* / Q000633:toxicity*; D010084:Oxidation-Reduction; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002492:Central Nervous System Depressants; D006213:Hallucinogens; D000431:Ethanol; D012313:RNA; D007770:L-Lactate Dehydrogenase; D019392:Cytochrome P-450 CYP2E1; D051544:Cytochrome P-450 CYP3A; D018817:N-Methyl-3,4-methylenedioxyamphetamine