Regulation of reductive processes by glutathione.
Regulation of reductive processes by glutathione.
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谷胱甘肽还原过程的调节。
DOI：
10.1016/0006-2952(86)90545-9
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发表时间：
1986
影响因子：
5.8
通讯作者：
Reed,DJ
中科院分区：
文献类型：
--
作者：
Reed,DJ
药物活化中的生物还原反应能够消耗细胞中相当大部分的NADPH还原 * 当量。这些反应通常利用这种还原当量进行生物还原，以将药物活化为不稳定的中间体，并通过谷胱甘肽还原当量还原如果药物中间体与分子氧反应所形成的过氧化氢或氢过氧化物。由于大鼠肝细胞和L-5178 Y淋巴瘤细胞中谷胱甘肽（GSH）的”静息”池大小约为NADPH的10倍[1，2]，因此GSH池对NADPH池的状态及其在药物代谢期间的细胞内利用具有重大影响。GSH不能提供药物诱导的过氧化氢的细胞解毒所必需的还原当量，其特征在于随着GSSG形成和流出发生谷胱甘肽耗竭。有关综述，请参见[2-4]。因此，谷胱甘肽可以在药物生物还原中发挥调节作用，因为对细胞产生NADPH还原当量的能力有很高的要求。本文将重点讨论NADPH和GSH中所含的还原当量在药物生物还原过程中提供非常动态的响应，以及谷胱甘肽氧化还原循环是为药物诱导的超氧化物和过氧化氢生物还原提供还原当量的主要途径。通过用二酰胺对L-5178 Y鼠淋巴瘤细胞进行稳态GSH氧化剂攻击而不损失细胞活力，已经证明了高水平GSH还原当量的持续（3-4小时）产生。以及脂肪酸的生物合成，都来源于几种脂肪酶的底物（表1）。Kauffman等人的类似数据。[5]表明异柠檬酸脱氢酶活性支持NADPH的主要利用，并且两种β-
Bio-reduction reactions in the activation of drugs are capable of consuming a significant fraction of the NADPH-reducing* equivalents in the cell. These reactions often utilize such reducing equivalents for bio-reduction to activate a drug to an unstable intermediate and to reduce, via glutathione-reducing equivalents, the hydrogen peroxide or hydroperoxide formed if the drug intermediate (s) reacts with molecular oxygen. Since the" resting" pool size of glutathione (GSH) in rat hepatocytes and in L-5178Y lymphoma cells is about 10-fold greater than that of NADPH [1, 2], the GSH pool has a major influence upon the status of the NADPH pool and its intracellular utilization during drug metabolism. Failure of GSH to provide the necessary reducing equivalents for cellular detoxication of drug-induced hydrogen peroxide is characterized by glutathione depletion as GSSG formation and efflux occurs. For reviews see [2–4]. Thus, glutathione can be given a regulatory role in drug bio-reduction due to the high demand that can be placed on cellular capacity to generate NADPH-reducing equivalents. This paper will focus on the evidence that the reducing equivalents contained in NADPH and GSH can provide very dynamic responses during bioreduction of drugs and that the glutathione redox cycle is the major pathway to provide the reducing equivalents for bio-reduction of drug-induced superoxide and hydrogen peroxide. Sustained (3-4 hr) production of high levels of GSH-reducing equivalents has been demonstrated by a steady state GSH oxidant challenge with diamide to L-5178Y murine lymphoma cells without loss of cell viability.NADPH GENERATION The reducing equivalents needed for the NADPH-dependent reactions, including those by NADPH-dependent bio-reductions that are catalyzed by cytochrome P-450 reductase, glutathione reductase, as well as fatty acid biosynthesis, are derived from substrates to several dehydrogenases (Table 1). Similar data by Kauffman et al.[5] suggest that isocitrate dehydrogenase activity supports the predominant utilization of NADPH and that the two dehydro-