期刊
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
卷 411, 期 1, 页码 145-157出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/S0003-9861(02)00716-6
关键词
DT-diaphorase; A549; oxidative stress; quinone; catalase; superoxide dismutase
资金
- NHLBI NIH HHS [HL37556, R01 HL037556] Funding Source: Medline
- NIEHS NIH HHS [R01 ES005511, ES05511, R56 ES005511, R01 ES005511-11] Funding Source: Medline
Cytotoxicity of 1,4-naphthoquinones has been attributed to intracellular reactive oxygen species (ROS) generation through one-electron-reductase-mediated redox cycling and to arylation of cellular nucleophiles. Here, however, we report that in a subclone of lung epithelial A549 cells (A549-S previously called A549-G4S (Watanabe, et al., Am. J. Physiol. 283 (2002) L726-736), the mechanism of ROS generation by menadione and by 2,3-dimethoxy-1,4-naphthoquinone (DMNQ), and therefore that of cytotoxicity, differs from the paradigm. Ninety percent of H2O2 generation by both the quinones can be prevented by dicumarol, an inhibitor of NAD(P)H quinone oxidoreductase (NQO1), at the submicromolar level, regardless of the quinone concentrations. Exogenous SOD also inhibits H2O2 production at low but not high concentrations of the quinones, especially DMNQ. Thus, at low quinone concentrations, superoxide-driven hydroquinone autoxidation accounts for more than half of H2O2 generation by both quinones, whereas at high quinone concentrations, especially for DMNQ, comproportionation-driven hydroquinone autoxidation becomes the predominant mechanism. Hydroquinone autoxidation appears to occur predominantly in the extracellular environment than in the cytosol as extracellular catalase can dramatically attenuate quinone-induced cytotoxicity throughout the range of quinone concentrations, whereas complete inactivation of endogenous catalase or complete depletion of intracellular glutathione has only a marginal effect on their cytotoxicity. Finally, we show evidence that ROS production is a consequence of the compensatory defensive role of NQO1 against quinone arylation. (C) 2003 Elsevier Science (USA). All rights reserved.
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