Is hyperthermia the triggering factor for hepatotoxicity induced by 3,4-methylenedioxymethamphetamine (ecstasy)? An in vitro study using freshly isolated mouse hepatocytes

The consumption of 3,4-methylenedioxymethamphetamine (ecstasy; MDMA) may ca use hepatocellular damage in humans, a toxic effect that has been increasin g in frequency in the last few years, although the underlying mechanisms ar e still unknown. The metabolism of MDMA involves the production of reactive metabolites which form adducts with intracellular nucleophilic sites, as i s the case with glutathione (GSH). Also, MDMA administration elicits hypert hermia, a potentially deleterious condition that may aggravate its direct t oxic effects. Thus, the objective of this study was to evaluate the extent of MDMA-induced depletion of GSH, induction of lipid peroxidation and loss of cell viability in freshly isolated mouse hepatocytes under normothermic conditions (37 degreesC) and to compare the results with the effects obtain ed under hyperthermic conditions (41 degreesC). By itself, hyperthermia was an important cause of cell toxicity. A rise in incubation temperature from 37 degreesC to 41 degreesC caused oxidative stress in freshly isolated mou se hepatocytes, reflected as a time-dependent induction of lipid peroxidati on and consequent loss of cell viability (up to 40-45%), although the varia tions in GSH and GSSG levels were similar to those under normothermic condi tions. MDMA (100, 200, 400, 800 and 1600 muM) induced a concentration- and time-dependent GSH depletion at 37 degreesC but had a negligible effect on lipid peroxidation and cell viability at this temperature. It is particular ly noteworthy that hyperthermia (41 degreesC) potentiated MDMA-induced depl etion of GSH, production of lipid peroxidation and loss of cell viability ( up to 90-100%). It is therefore concluded that hyperthermia potentiates MDM A-induced toxicity in freshly isolated mouse hepatocytes.