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首页> 外文期刊>Archives of Toxicology >Cytotoxic effects of 3,4-methylenedioxy-N-alkylamphetamines, MDMA and its analogues, on isolated rat hepatocytes
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Cytotoxic effects of 3,4-methylenedioxy-N-alkylamphetamines, MDMA and its analogues, on isolated rat hepatocytes

机译：3,4-亚甲二氧基-N-烷基苯丙胺，MDMA及其类似物对离体大鼠肝细胞的细胞毒性作用

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The amphetamine-derived designer drugs have been illegally used worldwide as recreational drugs, some of which are known to be hepatotoxic in humans. To compare their cytotoxic effects, 3,4-methylenedioxy-N-methamphetamine (MDMA) and its related analogues, N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine (MBDB), 3,4-(methylenedioxyphenyl)-2-butanamine (BDB) and 2-methylamino-1-(3,4-methylenedioxyphenyl)-propane-1-one (methylone) were studied in freshly isolated rat hepatocytes. MBDB caused not only concentration (0–4.0 mM)- and time (0–2 h)-dependent cell death accompanied by the formation of cell blebs, and the loss of cellular ATP and adenine nucleotide pools, and reduced glutathione levels, but also the accumulation of oxidized glutathione. Of the other analogues examined, the cytotoxicity of MBDB and BDB was greater than that of MDMA and methylone, suggesting that hepatotoxicity is generally induced by these drugs. In addition, DNA damage and the induction of reactive oxygen species were greater after the incubation of hepatocytes with MBDB (2 and 4 mM) than after that with MDMA. In isolated liver mitochondria, MBDB/BDB resulted in a greater increase in the rate of state 4 oxygen consumption than did MDMA/methylone, indicating an uncoupling effect and a decrease in the rate of state 3 oxygen consumption in a concentration dependent manner. Furthermore, MBDB resulted in mitochondrial swelling dependent on the mitochondrial permeability transition (MPT); the effect of MDMA was less than that of MBDB. Taken collectively, these results suggest that (1) the onset of cytotoxicity caused by designer drugs such as MBDB and MDMA is linked to mitochondrial failure dependent upon the induction of the MPT accompanied by mitochondrial depolarization and depletion of ATP through uncoupling of oxidative phosphorylation in rat hepatocytes, and (2) MBDB and MDMA elicit DNA damage, suggesting that nuclei as well as mitochondria are target sites of these compounds.
机译：苯丙胺衍生的名牌药物已在世界范围内非法用作娱乐性药物，其中有些已知对人体具有肝毒性。为了比较它们的细胞毒性作用，3,4-亚甲二氧基-N-甲基苯丙胺（MDMA）及其相关类似物N-甲基-1-（3,4-亚甲二氧基苯基）-2-丁胺（MBDB），3,4-（亚甲二氧基苯基） ）-2-丁胺（BDB）和2-甲基氨基-1-（3,4-亚甲基二氧苯基）-丙烷-1-酮（甲酮）在新鲜分离的大鼠肝细胞中进行了研究。 MBDB不仅引起浓度（0–4.0 mM）和时间（0–2 h）依赖性的细胞死亡，并伴随着细胞气泡的形成，细胞ATP和腺嘌呤核苷酸池的损失，谷胱甘肽水平降低，而且氧化型谷胱甘肽的积累。在检查的其他类似物中，MBDB和BDB的细胞毒性大于MDMA和甲酮的细胞毒性，这表明这些药物通常可诱导肝毒性。此外，MBDB（2和4 mM）孵育肝细胞后，DNA损伤和对活性氧的诱导要比MDMA孵育后更大。在分离的肝线粒体中，MBDB / BDB导致状态4耗氧率的增加比MDMA /甲酮更大，表明以浓度依赖性方式的解偶联作用和状态3耗氧率的降低。此外，MBDB导致线粒体肿胀取决于线粒体通透性转变（MPT）。 MDMA的影响小于MBDB。综上所述，这些结果表明：（1）设计药物如MBDB和MDMA引起的细胞毒性的发作与线粒体衰竭有关，依赖于MPT的诱导，伴随着线粒体去极化和ATP通过大鼠氧化磷酸化解偶联而耗竭ATP。 （2）MBDB和MDMA引起DNA损伤，表明核以及线粒体是这些化合物的靶位。

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