Role of oxidative stress and glutathione in busulfan toxicity in cultured murine hepatocytes
Role of oxidative stress and glutathione in busulfan toxicity in cultured murine hepatocytes
复制标题
DOI：
10.1159/000028359
复制
发表时间：
2000-01-01
期刊：
影响因子：
3.1
通讯作者：
Wang, XD
中科院分区：
文献类型：
--
作者：
DeLeve, LD;Wang, XD
这项研究考察了白丹的新陈代谢。体内给药和体外给药使肝细胞谷胱甘肽(GSH)含量分别降低60%和50%。体外实验中，谷胱甘肽S转移酶抑制剂或抗氧化剂均可阻止白丹的毒性，并导致氧化型谷胱甘肽和硫代巴比妥酸活性物质的产生增加。N，N-二(2-氯乙基)-N-亚硝脲(BCNU)可防止GSH前体的毒性。谷胱甘肽的耗竭加剧了毒性。在GSH耗竭的肝细胞中，白花丹使GSH降低了95%，而BCNU不阻止GSH前体的拯救。结论：(1)在GSH正常的肝细胞中，白花丹的毒性需要结合GSH，不会引起GSH的严重耗竭，并且是由氧化应激介导的。我们假设GSH结合物促进氧化应激。(2)在谷胱甘肽耗竭的肝细胞中：白花丹可深度消耗谷胱甘肽；毒性由氧化应激介导，并通过恢复谷胱甘肽水平来防止；细胞死亡可能是由于非对立的内源性氧化应激所致。版权所有(C)2000 S.Karger AG，巴塞尔。
This study examines busulfan metabolism. Busulfan given in vivo or in vitro decreased hepatocyte glutathione (GSH) by 60 and 50%, respectively. In vitro, busulfan toxicity was prevented by glutathione S-transferase inhibitors or by antioxidants and led to increased production of oxidized GSH and thiobarbituric acid reactive substances. 'Rescue' from toxicity by GSH precursors was prevented by N,N-bis(2-chloroethyl)-N-nitrosourea (BCNU). Depletion of GSH exacerbated toxicity. In GSH depleted hepatocytes, busulfan decreased GSH by 95% and BCNU did not prevent rescue by GSH precursors. Conclusions: (1) In hepatocytes with normal GSH: busulfan toxicity requires GSH conjugation, does not cause profound GSH depletion and is mediated by oxidative stress. We postulate that a GSH conjugate promotes oxidative stress. (2) In GSH-depleted hepatocytes: busulfan profoundly depletes GSH; toxicity is mediated by oxidative stress and is prevented by restoring GSH levels; cell death may be due to unopposed endogenous oxidative stress. Copyright (C) 2000 S. Karger AG, Basel.