Gp91phox-containing NAD(P)H oxidase increases superoxide fonnation by doxorubicin and NADPH

被引:92
作者
Deng, Shiwei
Kruger, Anke
Kleschyov, Andrei L.
Kalinowski, Leszek
Daiber, Andreas
Woinowski, Leszek
机构
[1] Johannes Gutenberg Univ Mainz, Dept Pharmacol, D-55101 Mainz, Germany
[2] Johannes Gutenberg Univ Mainz, Dept Cardiol, Med Clin 2, D-55101 Mainz, Germany
[3] Polish Acad Sci, Med Res Ctr, PL-00901 Warsaw, Poland
[4] Med Univ Gdansk, Dept Clin Chem & Biochem, Gdansk, Poland
关键词
doxorubicin; NADPH; superoxide; NAD(P)H oxidase; NADPH CYP450 reductase; INDUCED CARDIAC-HYPERTROPHY; NECROSIS-FACTOR-ALPHA; SMOOTH-MUSCLE-CELLS; ANGIOTENSIN-II; HEART-FAILURE; OXIDATIVE STRESS; ENDOTHELIAL DYSFUNCTION; INDUCED CARDIOTOXICITY; PRESSURE-OVERLOAD; HYDROGEN-PEROXIDE;
D O I
10.1016/j.freeradbiomed.2006.11.013
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Doxorubicin is a highly effective antineoplastic drug associated with a dose-dependent cardiotoxicity that may result in irreversible cardiomyopathy and heart failure. Gene variants of the superoxide-generating enzyme NAD(P)H oxidase have recently been associated with this phenotype. We investigated the mechanism of this association using lucigenin-enhanced chemiluminescence, spectrophotometry, electrochemical sensor, and electron paramagnetic resonance spectroscopy. Superoxide production was measured in female wild-type and NAD(P)H oxidase-deficient (gp91phox knockout) mice. The magnitude of the increase in superoxide production on the addition of doxorubicin was much higher in hearts of wild-type mice than in enzyme-deficient mice. An increase in superoxide production was observed also on the addition of the NADPH cytochrome P450 reductase. However, doxorubicin reacted with NADPH producing superoxide even in the absence of any enzymatic activity. Taken together, gp91phox-containing NAD(P)H oxidase and NADPH cytochrome P450 reductase can enhance superoxide production caused by the chemical interaction of doxorubicin and NADPH. These findings are in agreement with the recently reported reduced cardiotoxicity following doxorubicin treatment in gp91phox knockout mice and with associations between NAD(P)H oxidase gene variants and sensitivity to doxorubicin. (c) 2006 Elsevier Inc. All rights reserved.
引用
收藏
页码:466 / 473
页数:8
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