Intracellular GSH level is a factor in As4.1 juxtaglomerular cell death by arsenic trioxide.
Arsenic trioxide has been known to regulate many biological functions such as cell proliferation, apoptosis, differentiation, and angiogenesis in various cell lines. We investigated the involvement of GSH and ROS such as H(2)O(2) and O(2)(*-) in the death of As4.1 cells by arsenic trioxide. The intracellular ROS levels were changed depending on the concentration and length of incubation with arsenic trioxide. The intracellular O(2)(*-) level was significantly increased at all the concentrations tested. Arsenic trioxide reduced the intracellular GSH content. Treatment of Tiron, ROS scavenger decreased the levels of ROS in 10 microM arsenic trioxide-treated cells. Another ROS scavenger, Tempol did not decrease ROS levels in arsenic trioxide-treated cells, but slightly recovered the depleted GSH content and reduced the level of apoptosis in these cells. Exogenous SOD and catalase did not reduce the level of ROS, but did decrease the level of O(2)(*-). Both of them inhibited GSH depletion and apoptosis in arsenic trioxide-treated cells. In addition, ROS scavengers, SOD and catalase did not alter the accumulation of cells in the S phase induced by arsenic trioxide. Furthermore, JNK inhibitor rescued some cells from arsenic trioxide-induced apoptosis, and this inhibitor decreased the levels of O(2)(*-) and reduced the GSH depletion in these cells. In summary, we have demonstrated that arsenic trioxide potently generates ROS, especially O(2)(*-), in As4.1 juxtaglomerular cells, and Tempol, SOD, catalase, and JNK inhibitor partially rescued cells from arsenic trioxide-induced apoptosis through the up-regulation of intracellular GSH levels.
Han
Yong Hwan
YH
Department of Physiology, Medical School, Research Institute of Clinical Medicine, Center for Healthcare Technology Development, Chonbuk National University, Jeonju 561-180, Republic of Korea.
Kim
Sung Zoo
SZ
Kim
Suhn Hee
SH
Park
Woo Hyun
WH
D000818:Animals; D017209:Apoptosis; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D002374:Catalase; D002453:Cell Cycle; D016923:Cell Death; D016193:G1 Phase; D005978:Glutathione / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008822:Mice, Transgenic; D010087:Oxides / Q000494:pharmacology*; D010100:Oxygen / Q000737:chemistry; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase / Q000378:metabolism
D001152:Arsenicals; D010087:Oxides; D017382:Reactive Oxygen Species; D002374:Catalase; D013482:Superoxide Dismutase; D048670:MAP Kinase Kinase 4; D005978:Glutathione; D000077237:Arsenic Trioxide; D010100:Oxygen