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首页> 外文期刊>Journal of biochemical and molecular toxicology >Prevention of naphthalene-induced pulmonary toxicity by glutathione prodrugs: Roles for glutathione depletion in adduct formation and cell injury.
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Prevention of naphthalene-induced pulmonary toxicity by glutathione prodrugs: Roles for glutathione depletion in adduct formation and cell injury.

机译：谷胱甘肽前药预防萘诱发的肺毒性：谷胱甘肽耗竭在加合物形成和细胞损伤中的作用。

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Naphthalene is metabolized in the lung and liver to reactive intermediates by cytochrome P450 enzymes. These reactive species deplete glutathione, covalently bind to proteins, and cause necrosis in Clara cells of the lung. The importance of glutathione loss in naphthalene toxicity was investigated by using the glutathione prodrugs (glutathione monoethylester or cysteine-glutathione mixed disulfide) to maintain glutathione pools during naphthalene exposure. Mice given a single intraperitoneal injection of naphthalene (1.5 mmol/kg) were treated with either prodrug (2.5 mmol/kg) 30 min later. Both compounds effectively maintained glutathione levels and decreased naphthalene-protein adducts in the lung and liver. However, cysteine-glutathione mixed disulfide was more effective at preventing Clara cell injury. To study the prodrugs in Clara cells without the influence of hepatic naphthalene metabolism and circulating glutathione, dose-response and time-course studies were conducted with intrapulmonary airway explant cultures. Only the ester of glutathione raised GSH in vitro; however, both compounds limited protein adducts and cell necrosis. In vitro protection was not associated with decreased naphthalene metabolism. We conclude that (1) glutathione prodrugs can prevent naphthalene toxicity in Clara cells, (2) the prodrugs effectively prevent glutathione loss in vivo, and (3) cysteine-glutathione mixed disulfide prevents naphthalene injury in vitro without raising glutathione levels. (c) 2005 Wiley Periodicals, Inc. J Biochem Mol Toxicol 19:42-41, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20052.
机译：萘通过细胞色素P450酶在肺和肝中代谢为反应性中间体。这些反应性物质耗尽谷胱甘肽，与蛋白质共价结合，并在肺的克拉拉细胞中引起坏死。谷胱甘肽损失在萘毒性中的重要性已通过使用谷胱甘肽前药（谷胱甘肽单乙酯或半胱氨酸-谷胱甘肽混合二硫化物）来维持萘暴露过程中的谷胱甘肽池。腹膜内注射萘（1.5 mmol / kg）的小鼠在30分钟后用前药（2.5 mmol / kg）处理。两种化合物均能有效维持谷胱甘肽水平，并减少肺和肝中的萘蛋白加合物。然而，半胱氨酸-谷胱甘肽混合二硫化物在预防克拉拉细胞损伤方面更有效。为了研究克拉拉细胞中的前药不受肝萘代谢和循环谷胱甘肽的影响，对肺内气管外植体培养物进行了剂量反应和时程研究。在体外只有谷胱甘肽的酯能增加谷胱甘肽。然而，这两种化合物都限制了蛋白质加合物和细胞坏死。体外保护与萘代谢下降无关。我们得出的结论是：（1）谷胱甘肽前药可以预防Clara细胞中萘的毒性;（2）前药可以有效地预防体内谷胱甘肽的损失;（3）半胱氨酸-谷胱甘肽混合的二硫化物可以在不增加谷胱甘肽水平的情况下防止萘的体外损伤。 （c）2005 Wiley Periodicals，Inc. J Biochem Mol Toxicol 19：42-41，2005;在线发布于Wiley InterScience（www.interscience.wiley.com）。 DOI 10.1002 / jbt.20052。

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