Faculty Collaboration Database

L-Xylulose reductase is involved in 9,10-phenanthrenequinone-induced apoptosis in human T lymphoma cells. Free Radic Biol Med 2008 Mar 15;44(6):1191-202

Date

01/22/2008

Pubmed ID

18206670

DOI

10.1016/j.freeradbiomed.2007.12.024

Scopus ID

2-s2.0-39949085604 (requires institutional sign-in at Scopus site)   54 Citations

Abstract

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 alpha-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.

Author List

Matsunaga T, Kamiya T, Sumi D, Kumagai Y, Kalyanaraman B, Hara A

Author

Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Air Pollutants
Apoptosis
Blotting, Western
Caspases
Cell Line, Tumor
Flow Cytometry
Humans
Membrane Potential, Mitochondrial
Oxidoreductases
Phenanthrenes
RNA, Messenger
Reactive Oxygen Species
Reverse Transcriptase Polymerase Chain Reaction
T-Lymphocytes