Endothelial Nitric Oxide Synthase-Dependent Superoxide Generation from Adriamycin
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- 作者：Jeannette Vá ; squez-Vivar ; Pavel Martasek ; Neil Hogg ; Bettie Sue Siler Masters ; Kirkwood A. Pritchard ; Jr. ; and B. Kalyanaraman
- 刊名：Biochemistry
- 出版年：1997
- 出版时间：September 23, 1997
- 年：1997
- 卷：36
- 期：38
- 页码：11293 - 11297
- 全文大小：119K
- 年卷期：v.36,no.38(September 23, 1997)
- ISSN：1520-4995
文摘
Adriamycin (or doxorubicin) is an active andbroad spectrum chemotherapeutic agent.Unfortunately, its clinical use is severely restricted by adose-limiting cardiotoxicity which has been linkedto the formation of superoxide. Enzymatic one-electron reductionof adriamycin forms adriamycinsemiquinone radical, which rapidly reacts with oxygen to formsuperoxide and adriamycin. In this way,adriamycin provides a kinetic mechanism for the one-electron reductionof oxygen by flavoenzymes suchas NADPH-cytochrome P450 reductase and mitochondrial NADHdehydrogenase. We demonstrate herethat the endothelial isoform of nitric oxide synthase (eNOS) reducesadriamycin to the semiquinone radical.As a consequence, superoxide formation is enhanced and nitricoxide production is decreased. Adriamycinbinds to eNOS with a Km of approximately 5 
M,as calculated from both eNOS-dependent NADPHconsumption and superoxide generation. Adriamycin stimulatedsuperoxide formation is not affected bycalcium/calmodulin and is abolished by the flavoenzyme inhibitor,diphenyleneiodonium. This stronglysuggests that adriamycin undergoes reduction at the reductase domain ofeNOS. A consequence of eNOS-mediated reductive activation of adriamycin is the disruption of thebalance between nitric oxide andsuperoxide. This may lead eNOS to generate peroxynitrite andhydrogen peroxide, potent oxidantsimplicated in several vascular pathologies.
M,as calculated from both eNOS-dependent NADPHconsumption and superoxide generation. Adriamycin stimulatedsuperoxide formation is not affected bycalcium/calmodulin and is abolished by the flavoenzyme inhibitor,diphenyleneiodonium. This stronglysuggests that adriamycin undergoes reduction at the reductase domain ofeNOS. A consequence of eNOS-mediated reductive activation of adriamycin is the disruption of thebalance between nitric oxide andsuperoxide. This may lead eNOS to generate peroxynitrite andhydrogen peroxide, potent oxidantsimplicated in several vascular pathologies.