The clinical use of the quinone-containing chemotherapeutic agent adriamycin is restricted by a severe dose-dependent cardiotoxicity. The mechanism underlying cytotoxicity has been linked to an increased generation of superoxide. The NAD(P)H-dependent enzymatic one-electron reduction of adriamycin generates the adriamycin semiquinone radical which undergoes redox-cycling in the presence of oxygen to generate superoxide and adriamycin. Thereby adriamycin provides a kinetic mechanism for one-electron reduction of oxygen by NAD(P)H. Here we show that endothelial nitric oxide synthase (eNOS) stimulates the generation of superoxide from adriamycin. Adriamycin binds to eNOS with a Km of approx. 5.0 micromole as determined from NADPH consumption and ESR spin-trapping of superoxide. Superoxide generation from eNOS/adriamycin is not dependent on the presence of CA(2+)/CaM and is abolished by the flavoprotein inhibitor dephenyleneiodonium. This strongly suggests that adriamycin undergoes reduction at the reductase domain of eNOS. One of the consequences of eNOS-mediated reductive activation of adriamycin is decreased production of nitric oxide and increased superoxide formation. This may lead eNOS to generate peroxynitrite, a potent oxidant implicated in several vascular pathologies.?

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR001008-23
Application #
6279860
Study Section
Project Start
1998-04-01
Project End
1999-02-28
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
23
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Medical College of Wisconsin
Department
Type
DUNS #
073134603
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
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Sheng, Zhi-Guo; Huang, Wei; Liu, Yu-Xiang et al. (2013) Ofloxacin induces apoptosis via ?1 integrin-EGFR-Rac1-Nox2 pathway in microencapsulated chondrocytes. Toxicol Appl Pharmacol 267:74-87
Sheng, Zhi-Guo; Huang, Wei; Liu, Yu-Xiang et al. (2013) Bisphenol A at a low concentration boosts mouse spermatogonial cell proliferation by inducing the G protein-coupled receptor 30 expression. Toxicol Appl Pharmacol 267:88-94
Liddle, Brendan J; Wanniarachchi, Sarath; Hewage, Jeewantha S et al. (2012) Electronic communication across diamagnetic metal bridges: a homoleptic gallium(III) complex of a redox-active diarylamido-based ligand and its oxidized derivatives. Inorg Chem 51:12720-8

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