Is hyperthermia the triggering factor for hepatotoxicity induced by 3,4-methylenedioxymethamphetamine (ecstasy)? An in vitro study using freshly isolated mouse hepatocytes
Is hyperthermia the triggering factor for hepatotoxicity induced by 3,4-methylenedioxymethamphetamine (ecstasy)? An in vitro study using freshly isolated mouse hepatocytes
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DOI：
10.1007/s002040000200
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发表时间：
2001-02-01
影响因子：
6.1
通讯作者：
Bastos, ML
中科院分区：
文献类型：
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作者：
Carvalho, M;Carvalho, F;Bastos, ML
食用 3,4-亚甲二氧基甲基苯丙胺（摇头丸；MDMA）可能会导致人类肝细胞损伤，这种毒性作用在过去几年中越来越频繁，但其潜在机制仍不清楚。 MDMA 的代谢涉及反应性代谢物的产生，这些代谢物与细胞内亲核位点形成加合物，就像谷胱甘肽 (GSH) 的情况一样。此外，服用 MDMA 会引起体温过高，这是一种潜在的有害状况，可能会加剧其直接毒性作用。因此，本研究的目的是评估常温条件（37℃）下MDMA诱导的GSH消耗、诱导脂质过氧化和细胞活力丧失的程度，并将结果与高温条件（41℃）下获得的效果进行比较。就其本身而言，过高热是细胞毒性的一个重要原因。培养温度从 37°C 升高至 41°C 会导致新鲜分离的小鼠肝细胞发生氧化应激，表现为脂质过氧化的时间依赖性诱导以及随后的细胞活力丧失（高达 40-45%），尽管 GSH 和 GSSG 水平的变化与常温条件下的变化相似。 MDMA（100、200、400、800 和 1600 muM）在 37 摄氏度下诱导浓度和时间依赖性的 GSH 消耗，但在此温度下对脂质过氧化和细胞活力的影响可以忽略不计。特别值得注意的是，高温（41 摄氏度）会加剧 MDMA 诱导的 GSH 消耗、脂质过氧化的产生和细胞活力的丧失（高达 90-100%）。因此得出的结论是，高温会增强 MDMA 在新鲜分离的小鼠肝细胞中诱导的毒性。
The consumption of 3,4-methylenedioxymethamphetamine (ecstasy; MDMA) may cause hepatocellular damage in humans, a toxic effect that has been increasing in frequency in the last few years, although the underlying mechanisms are still unknown. The metabolism of MDMA involves the production of reactive metabolites which form adducts with intracellular nucleophilic sites, as is the case with glutathione (GSH). Also, MDMA administration elicits hyperthermia, a potentially deleterious condition that may aggravate its direct toxic 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 obtained 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 mouse hepatocytes, reflected as a time-dependent induction of lipid peroxidation and consequent loss of cell viability (up to 40-45%), although the variations in GSH and GSSG levels were similar to those under normothermic conditions. 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 particularly noteworthy that hyperthermia (41 degreesC) potentiated MDMA-induced depletion of GSH, production of lipid peroxidation and loss of cell viability (up to 90-100%). It is therefore concluded that hyperthermia potentiates MDMA-induced toxicity in freshly isolated mouse hepatocytes.