L-Xylulose reductase is involved in 9,10-phenanthrenequinone-induced apoptosis in human T lymphoma cells
- 作者：Toshiyuki Matsunaga ; Tetsuro Kamiya ; Daigo Sumi ; Yoshito Kumagai ; B. Kalyanaraman ; Akira Hara
- 关键词：9 ; 10-Phenanthrenequinone ; T lymphoma ; l-Xylulose reductase ; Oxidative stress ; Free radicals
- 刊名：Free Radical Biology and Medicine
- 出版年：2008
- 期刊代码：105_08915849
- 类别：med
- 出版时间：15 March 2008
- 卷：44
- 期：6
- 页码：1191-1202
- 文件大小：960 K
摘要
9,10-Phenanthrenequinone (9,10-PQ), a major component in diesel exhaust particles, is suggested to generate reactive oxygen species (ROS) through its redox cycling, leading to cell toxicity. l-Xylulose reductase (XR), a NADPH-dependent enzyme in the uronate pathway, strongly reduces 
-dicarbonyl compounds and was thought to act as a detoxification enzyme against reactive carbonyl compounds. Here, we have investigated the role of intracellular ROS generation in apoptotic signaling in human acute T-lymphoblastic leukemia MOLT-4 cells treated with 9,10-PQ and the role of XR in the generation of ROS. Treatment with 9,10-PQ elicited not only apoptotic signaling, including mitochondrial membrane dysfunction and activation of caspases and poly(ADP-ribose) polymerase, but also intracellular ROS generation and consequent glutathione depletion. The apoptotic effects of 9,10-PQ were drastically mitigated by pretreatment with intracellular ROS scavengers, such as N-acetyl-l-cysteine, glutathione monoethyl ester, and polyethylene glycol-conjugated catalase, indicating that intracellular ROS generation is responsible for the 9,10-PQ-evoked apoptosis. Surprisingly, the ROS generation and cytotoxicity by 9,10-PQ were augmented in an XR-transformed cell line. XR indeed reduced 9,10-PQ and produced superoxide anion through redox cycling. In addition, the expression levels of XR and its mRNA in the T lymphoma cells were markedly enhanced after the exposure to 9,10-PQ, and the induction was completely abolished by the ROS scavengers. Moreover, the 9,10-PQ-induced apoptosis was partially inhibited by the pretreatment with XR-specific inhibitors. These results suggest that initially produced ROS induce XR, which accelerates the generation of ROS.
-dicarbonyl compounds and was thought to act as a detoxification enzyme against reactive carbonyl compounds. Here, we have investigated the role of intracellular ROS generation in apoptotic signaling in human acute T-lymphoblastic leukemia MOLT-4 cells treated with 9,10-PQ and the role of XR in the generation of ROS. Treatment with 9,10-PQ elicited not only apoptotic signaling, including mitochondrial membrane dysfunction and activation of caspases and poly(ADP-ribose) polymerase, but also intracellular ROS generation and consequent glutathione depletion. The apoptotic effects of 9,10-PQ were drastically mitigated by pretreatment with intracellular ROS scavengers, such as N-acetyl-l-cysteine, glutathione monoethyl ester, and polyethylene glycol-conjugated catalase, indicating that intracellular ROS generation is responsible for the 9,10-PQ-evoked apoptosis. Surprisingly, the ROS generation and cytotoxicity by 9,10-PQ were augmented in an XR-transformed cell line. XR indeed reduced 9,10-PQ and produced superoxide anion through redox cycling. In addition, the expression levels of XR and its mRNA in the T lymphoma cells were markedly enhanced after the exposure to 9,10-PQ, and the induction was completely abolished by the ROS scavengers. Moreover, the 9,10-PQ-induced apoptosis was partially inhibited by the pretreatment with XR-specific inhibitors. These results suggest that initially produced ROS induce XR, which accelerates the generation of ROS.