Nitric oxide protects against alkyl peroxide-mediated cytotoxicity: further insights into the role nitric oxide plays in oxidative stress.
Endogenously formed nitric oxide (NO) possesses diverse properties such as regulating physiological functions, exerting specific toxic effects, and protecting against various toxic substances. Recent studies suggest that in the presence of reactive oxygen species, NO can serve as an antioxidant. We show here that NO delivered from the NO donor compound, PAPA/NO (NH2(C3H6)(N[N(O)NO](C3H7)), protects Chinese hamster V79 lung fibroblasts from the cytotoxicity of t-butyl hydroperoxide and cumene hydroperoxide. In contrast, the other end products of PAPA/NO degradation in aqueous solution, NH2(C3H6)NH(C3H7) and nitrite, did not protect. The NONOate DEA/NO releases NO six times faster than PAPA/NO, yet did not afford protection, which implies that NO must be present throughout the alkyl hydroperoxide exposure. Measurements of NO concentrations released from PAPA/NO suggest that micromolar levels protect against cytotoxicity induced by alkyl hydroperoxides. These findings demonstrate that the flux of NO sustained over the duration of the peroxide exposure determines protection and not the total of NO delivered. These results suggest that concentrations of NO produced in the microenvironment of endothelial cells are high enough to protect cells from Fenton-type-mediated toxicity and support the premise that NO may exert a salutary effect in certain diseases associated with membrane damage.
Wink
D A
DA
Chemistry Section, National Cancer Institute, Frederick Cancer Research and Development Center, Maryland 21702, USA.
Cook
J A
JA
Krishna
M C
MC
Hanbauer
I
I
DeGraff
W
W
Gamson
J
J
Mitchell
J B
JB
D000477:Alkylating Agents / Q000494:pharmacology*; D000818:Animals; D016923:Cell Death; D002460:Cell Line / Q000187:drug effects; D002470:Cell Survival; D006224:Cricetinae; D003412:Cricetulus; D009569:Nitric Oxide / Q000378:metabolism*; D018384:Oxidative Stress; D010545:Peroxides / Q000494:pharmacology*
D000477:Alkylating Agents; D010545:Peroxides; D009569:Nitric Oxide