Ray Atish, Chatterjee Sarmishtha, Mukherjee Sandip, Bhattacharya Shelley
Environmental Toxicology Laboratory, Department of Zoology, Centre for Advanced Studies, Visva-Bharati (A Central University), Santiniketan, 731235, India.
Biometals. 2014 Jun;27(3):483-94. doi: 10.1007/s10534-014-9722-y. Epub 2014 Mar 15.
Glutathione reductase (GR) is an essential enzyme which maintains the reduced state of a cell. Therefore GR malfunction is closely associated with several disorders related to oxidative damage. The present study reports toxic manifestation of arsenic trioxide in respect of GR leading to apoptosis. Isolated rat hepatocytes exposed to arsenic trioxide were analyzed for GR expression and activity. Arsenic resulted in a time dependent inhibition of GR mediated by the superoxide anion. The cellular demand of functional enzyme is achieved by concomitant rise in gene expression. However, direct inhibition of GR by arsenic trioxide was also evident. Furthermore, arsenic induced free radical mediated inhibition of GR was found to be partially uncompetitive and associated with time dependent decrease in the substrate binding rate. Externalization of phosphatidylserine, nuclear degradation, apoptosis inducing factor leakage, apoptosome formation, caspase activation, DNA damage and break down of PARP suggest consequential induction of apoptosis due to inhibition of GR. The implication of GR was further established from the reduced rate of caspase activation in the arsenic trioxide treated cell, supplemented with complete and incomplete enzyme systems.
谷胱甘肽还原酶（GR）是一种维持细胞还原状态的必需酶。因此，GR功能异常与多种氧化损伤相关疾病密切相关。本研究报道了三氧化二砷对GR的毒性表现，进而导致细胞凋亡。对暴露于三氧化二砷的离体大鼠肝细胞进行GR表达和活性分析。三氧化二砷通过超氧阴离子介导对GR产生时间依赖性抑制作用。功能性酶的细胞需求通过基因表达的相应增加来实现。然而，三氧化二砷对GR的直接抑制作用也很明显。此外，发现三氧化二砷诱导的自由基介导的GR抑制作用部分为非竞争性，且与底物结合率的时间依赖性降低有关。磷脂酰丝氨酸外化、核降解、凋亡诱导因子泄漏、凋亡小体形成、半胱天冬酶激活、DNA损伤和聚ADP核糖聚合酶（PARP）分解表明，由于GR受到抑制，从而导致细胞凋亡。在补充了完整和不完整酶系统的三氧化二砷处理细胞中，半胱天冬酶激活率降低，进一步证实了GR的作用。
