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首页> 外文期刊>Archives of Toxicology >Structural isomerization of synephrine influences its uptake and ensuing glutathione depletion in rat-isolated cardiomyocytes.
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Structural isomerization of synephrine influences its uptake and ensuing glutathione depletion in rat-isolated cardiomyocytes.

机译：辛弗林的结构异构化影响其在大鼠分离的心肌细胞中的摄取并导致谷胱甘肽耗竭。

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Synephrine is a natural compound, frequently added to ephedra-free dietary supplements for weight-loss, due to its effects as a nonspecific adrenergic agonist. Though only p-synephrine has been documented in plants, the presence of m-synephrine has also been reported in weight-loss products. The use of synephrine in dietary supplements was accompanied by reports of adverse effects, especially at the cardiovascular level. It is well known that the imbalance in cardiac glutathione levels can increase the risk of cardiomyopathy. The present work aimed to study the role of organic cation-mediated transport of m- and p-synephrine and the possibility that p- and m-synephrine induce intracellular changes in glutathione levels in calcium-tolerant freshly isolated cardiomyocytes from adult rat. After a 3 h incubation with 1 mM p- or m-synephrine, the intracellular content of synephrine was measured by gas chromatography/ion trap-mass spectrometry (GC/IT-MS); cell viability and intracellular glutathione levels were also determined. To evaluate the potential protective effects of antioxidants against the adverse effects elicited by m-synephrine, cells were pre-incubated for 30 min with Tiron (100 muM) or N-acetyl-cysteine (NAC) (1 mM). To assess the influence of alpha(1)-adrenoceptors activation in glutathione depletion, a study with prazosin (100 nM) was also performed. The results obtained provide evidence that organic cation transporters OCT3 and OCT1 play a major role in m- and p-synephrine-mediated transport into the cardiomyocytes. The importance of these transporters seems similar for both isomers, although p-synephrine enters more into the cardiomyocytes. Furthermore, only m-synephrine induced intracellular total glutathione (GSHt) and reduced glutathione (GSH) depletion. NAC and Tiron were able to counteract the m-synephrine-induced GSH and GSHt decrease. On the other hand, the incubation with prazosin was not able to change m-synephrine-induced glutathione depletion showing that this effect is independent of alpha(1)-adrenoceptor stimulation. In conclusion, both positional isomers require OCT3 and OCT1-mediated transport to enter into the cardiomyocytes; however, the hydroxyl group in the p-position favours the OCT-mediated transport into cardiomyocytes. Furthermore, the structural isomerization of synephrine influences its toxicological profile since only m-synephrine caused GSH depletion.
机译：Synephrine是一种天然化合物，由于其作为非特异性肾上腺素能激动剂的作用，经常添加到不含麻黄的膳食补充剂中以减轻体重。尽管在植物中仅记录了对-正肾上腺素，但减肥产品中也有间-正肾上腺素的报道。在饮食补充剂中使用辛弗林伴随有不良反应的报道，尤其是在心血管方面。众所周知，心脏谷胱甘肽水平的失衡会增加患心肌病的风险。目前的工作旨在研究有机阳离子介导的间苯二酚和对炔苯丙氨酸的转运的作用，以及对成年大鼠耐钙的新鲜分离的心肌细胞中谷胱甘肽水平的影响。与1 mM对-或间-辛炔碱孵育3小时后，通过气相色谱/离子阱质谱（GC / IT-MS）测量肾上腺素的细胞内含量。还测定了细胞活力和细胞内谷胱甘肽水平。为了评估抗氧化剂对抗间苯二酚引起的不良反应的潜在保护作用，将细胞与Tiron（100μM）或N-乙酰半胱氨酸（NAC）（1 mM）预孵育30分钟。为了评估α（1）-肾上腺素受体激活对谷胱甘肽耗竭的影响，还进行了哌唑嗪（100 nM）的研究。获得的结果提供了证据，有机阳离子转运蛋白OCT3和OCT1在间-和对-Synephrine介导的心肌细胞转运中起主要作用。这些转运蛋白的重要性对于两种异构体而言似乎相似，尽管对炔肾上腺素会更多地进入心肌细胞。此外，仅间炔可以诱导细胞内总谷胱甘肽（GSHt）和减少谷胱甘肽（GSH）消耗。 NAC和Tiron能够抵消m-Synephrine诱导的GSH和GSHt降低。另一方面，与哌唑嗪的孵育不能改变间-丝氨酸诱导的谷胱甘肽耗竭，表明这种作用独立于α（1）-肾上腺素受体刺激。总之，两种位置异构体均需要OCT3和OCT1介导的转运才能进入心肌细胞。然而，对位的羟基有利于OCT介导的向心肌细胞的转运。此外，由于仅间丝肾上腺素引起GSH耗竭，因此辛弗林的结构异构化会影响其毒理学特征。

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