Neuronal nitric oxide synthase (NNOS) catalyzes one-electron reduction of 2,4,6-trinitrotoluene, resulting in decreased nitric oxide production and increased nNOS gene expression: implication for oxidative stress

Free Radical Biology & Medicine
Y KumagaiManabu Kunimoto

Abstract

To determine the mechanism of 2,4,6-trinitrotoluene (TNT)-induced oxidative stress involving neuronal nitric oxide synthase (nNOS), we examined alterations in enzyme activity and gene expression of nNOS by TNT, with an enzyme preparation and rat cerebellum primary neuronal cells. TNT inhibited nitric oxide formation (IC(50) = 12.4 microM) as evaluated by citrulline formation in a 20,000 g cerebellar supernatant preparation. A kinetic study revealed that TNT was a competitive inhibitor with respect to NADPH and a noncompetitive inhibitor with respect to L-arginine. It was found that purified nNOS was capable of reducing TNT, with a specific activity of 3900 nmol of NADPH oxidized/mg/min, but this reaction required CaCl(2)/calmodulin (CaM). An electron spin resonance (ESR) study indicated that superoxide (O(2)(.-)) was generated during reduction of TNT by nNOS. Exposure of rat cerebellum primary neuronal cells to TNT (25 microM) caused an intracellular generation of H(2)O(2), accompanied by a significant increase in nNOS mRNA levels. These results indicate that CaM-dependent one-electron reduction of TNT is catalyzed by nNOS, leading to a reduction in NO formation and generation of H(2)O(2) derived from O(2)(.-). Thus, it is sugg...Continue Reading

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Citations

Jun 1, 2010·Environmental Monitoring and Assessment·Julio FuchsNorma Casabé
Aug 1, 2013·Environmental Science & Technology·Jacob K StanleyNatàlia Garcia-Reyero
May 11, 2011·Proceedings of the National Academy of Sciences of the United States of America·Daniel A HellerMichael S Strano
May 7, 2008·Biochemistry. Biokhimii︠a︡·E A NaumenkoR P Naumova
Sep 5, 2015·Science·Emily J JohnstonNeil C Bruce
Jun 30, 2009·Biological Psychiatry·Stefania SchiavoneKarl-Heinz Krause
Mar 21, 2007·The FEBS Journal·Germaine EscamesDarío Acuña-Castroviejo
Jan 10, 2018·Frontiers in Microbiology·Irina V KhilyasOlga N Ilinskaya
Aug 28, 2021·International Journal of Molecular Sciences·Narimantas ČėnasLidija Kosychova
Jul 7, 2007·Environmental Science & Technology·Vanesa B TognettiAndrea M Smania

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