MECHANISMS OF TOXICITY OF 2-HYDROXY-1,4-NAPHTHOQUINONE AND 5-HYDROXY-1,4-NAPHTHOQUINONE - ABSENCE OF A ROLE FOR REDOX CYCLING IN THE TOXICITY OF 2-HYDROXY-1,4-NAPHTHOQUINONE TO ISOLATED HEPATOCYTES
MECHANISMS OF TOXICITY OF 2-HYDROXY-1,4-NAPHTHOQUINONE AND 5-HYDROXY-1,4-NAPHTHOQUINONE - ABSENCE OF A ROLE FOR REDOX CYCLING IN THE TOXICITY OF 2-HYDROXY-1,4-NAPHTHOQUINONE TO ISOLATED HEPATOCYTES
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DOI：
10.1002/jat.2550070209
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发表时间：
1987-04-01
影响因子：
3.3
通讯作者：
COHEN, GM
中科院分区：
文献类型：
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作者：
DOHERTY, MD;RODGERS, A;COHEN, GM
本文研究了两种结构相似的萘醌类化合物对离体大鼠肝细胞的毒性机制。5-OH-1，4-萘醌（5-OH-1，4-NQ;胡桃醌）和2-OH-1，4-萘醌（2-OH-1，4-NQ;指甲花醌）均对肝细胞产生浓度依赖性细胞毒性，在此之前细胞内谷胱甘肽耗竭。当在4°C或37°C下孵育时，5-OH-1，4-NQ引起细胞内谷胱甘肽的消耗，而当肝细胞在37°C下孵育时，2-OH-1，4-NQ引起细胞内谷胱甘肽的消耗，但在4°C下不引起。5-OH-1，4-NQ而非2-OH-1，4-NQ在缓冲溶液中与谷胱甘肽反应。这些结果表明，2-OH-1，4-NQ对细胞内谷胱甘肽的消耗是酶介导的，而在5-OH-1，4-NQ的情况下，与谷胱甘肽的直接化学反应可能是导致消耗的主要原因。已提出蛋白质硫醇的消耗在甲萘醌诱导的细胞毒性中的关键作用。与早期的工作一致，甲萘醌在细胞死亡之前引起蛋白质巯基的减少，然而，在2-OH-1，4-NQ和5-OH-1，4-NQ的细胞毒性浓度下，这种减少仅伴随而不是细胞死亡前的细胞死亡。5-OH-1，4-NQ的毒性机制与其他萘醌类似，涉及形成其相应的萘醌，活性氧和氧化还原循环，因为它刺激微粒体NADPH氧化和耗氧量不成比例地增加。在微粒体或肝细胞中均未获得2-OH-1，4-NQ氧化还原循环的证据，因此其细胞毒性必须涉及与目前提出的其他萘醌不同的机制。2-OH-1，4-NQ无法进行氧化还原循环可能是由于其单电子还原电位非常低（E1/7 - 415 mV）。因此，它是细胞还原酶还原成半醌的非常差的底物。
The mechanisms of toxicity to isolated rat hepatocytes of two structurally related naphthoquinones have been studied. Both 5‐OH‐1,4‐naphthoquinone (5‐OH‐1,4‐NQ; juglone) and 2‐OH‐1,4‐naphthoquinone (2‐OH‐1,4‐NQ; lawsone) caused a concentration‐dependent cytotoxicity to hepatocytes which was preceded by a depletion of intracellular glutathione. 5‐OH‐1,4‐NQ caused a depletion of intracellular glutathione when incubated either at 4°C or 37°C whereas 2‐OH‐1,4‐NQ caused a depletion of intracellular glutathione when the hepatocytes were incubated at 37°C but not at 4°C. 5‐OH‐1,4‐NQ but not 2‐OH‐1,4‐NQ reacted with glutathione in buffered solution. These results suggested that the depletion of intracellular glutathione by 2‐OH‐1,4‐NQ is enzyme mediated whereas in the case of 5‐OH‐1,4‐NQ the direct chemical reaction with glutathione may be largely responsible for the depletion. A critical role for depletion of protein thiols in menadione‐induced cytotoxicity has been proposed. In agreement with earlier work, menadione caused a decrease in protein sulphydryls prior to cell death, however, at cytotoxic concentrations of both 2‐OH‐1,4‐NQ and 5‐OH‐1,4‐NQ this decrease only accompanied rather than preceeded cell death.The mechanism of toxicity of 5‐OH‐1,4‐NQ is similar to that of other naphthoquinones and involves formation of its corresponding naphthosemiquinone, active oxygen species and redox cycling as it stimulated a disproportionate increase in both microsomal NADPH oxidation and oxygen consumption. No evidence for redox cycling of 2‐OH‐1,4‐NQ was obtained either with microsomes or hepatocytes and thus its cytotoxicity must involve a different mechanism to that currently proposed for other naphthoquinones. This inability of 2‐OH‐1,4‐NQ to redox cycle may be due to its very low one‐electron reduction potential (E1/7‐415 mV). Thus, it is a very poor substrate for reduction to a semiquinone by cellular reductases.