Kinetic Analysis of Intracellular Concentrations of Reactive Nitrogen Species
Open accessAbstract
Reactive nitrogen species derived from NO have been implicated in cancer and other diseases, but their intracellular concentrations are largely unknown. To estimate them under steady-state conditions representative of inflamed tissues, a kinetic model was developed that included the effects of cellular antioxidants, amino acids, proteins, and lipids. For an NO concentration of 1 microM, total peroxynitrite (Per, the sum of ONOO(-) and ONOOH), NO(2)(*), and N(2)O(3) were calculated to have concentrations in the nanomolar, picomolar, and femtomolar ranges, respectively. The concentrations of NO(2)(*) and N(2)O(3) were predicted to decrease markedly with increases in glutathione (GSH) levels, due to the scavenging of each by GSH. Although lipids accelerate the oxidation of NO by O(2) (because of the high solubility of each in hydrophobic media), lipid-phase reactions were calculated to have little effect on NO(2)(*) or N(2)O(3) concentrations. The major sources of intracellular NO(2)(*) were found to be the reaction of Per with metals and with CO(2), whereas the major sinks were its reactions with GSH and ascorbate (AH(-)). The radical-scavenging ability of GSH and AH(-) caused 3-nitrotyrosine to be the only tyrosine derivative predicted to be formed at a significant rate. The major GSH reaction product was S-nitrosoglutathione. Analytical (algebraic) expressions are provided for the concentrations of the key reactive intermediates, allowing the calculations to be extended readily.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Mice partially or conditionally lacking MnSOD showed dilated cardiomyopathy characterized by left ventricle dilation, decreased wall thickness, and hypertrophy.
“Further, mice partially or conditionally lacking MnSOD showed dilated cardiomyopathy characterized by left ventricle dilation, decreased wall thickness, and hypertrophy (584, 696).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [584]
Mice completely lacking MnSOD died within weeks of birth.
“Mice completely lacking MnSOD, leading to greater mitochondrial superoxide concentrations, died within weeks of birth (584), confirming the essentiality of mitochondrial superoxide scavenging.”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [584]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Nitric oxide: physiology, pathophysiology, and pharmacology.
Moncada, S., Palmer, R. M., & Higgs, E. A. (1991) · Pharmacological Reviews · doi:10.1016/s0031-6997(25)06663-3 · Cited by 15,525 · see citing works
Free Radicals in Biology and Medicine
Halliwell, B., & Gutteridge, J. M. C. (2015) · doi:10.1093/acprof:oso/9780198717478.001.0001 · Cited by 8,990 · see citing works
Roos, A., & Boron, W. F. (1981) · Physiological Reviews · doi:10.1152/physrev.1981.61.2.296 · Cited by 2,511 · see citing works
Physiological concentrations of purines and pyrimidines
Traut, T. W. (1994) · Molecular and Cellular Biochemistry · doi:10.1007/bf00928361 · Cited by 1,867 · see citing works
Nitric oxide, oxidants, and protein tyrosine nitration
Radí, R. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0307446101 · Cited by 1,456 · see citing works
Nitric oxide circulates in mammalian plasma primarily as an S-nitroso adduct of serum albumin.
Stamler, J. S., Jaraki, O., Osborne, J., Simon, D. I., Keaney, J., Vita, J., Singel, D., Valeri, C. R., & Loscalzo, J. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.16.7674 · Cited by 1,238 · see citing works
DNA damage and mutation in human cells exposed to nitric oxide in vitro.
Nguyen, T., Brunson, D. C., Crespi, C. L., Penman, B. W., Wishnok, J. S., & Tannenbaum, S. R. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.7.3030 · Cited by 972 · see citing works
Atom/Fragment Contribution Method for Estimating Octanol–Water Partition Coefficients
Meylan, W. M., & Howard, P. H. (1995) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600840120 · Cited by 862 · see citing works
Intracellular free amino acid concentration in human muscle tissue.
Bergström, J., Fürst, P., Norée, L. O., & Vinnars, E. (1974) · Journal of Applied Physiology · doi:10.1152/jappl.1974.36.6.693 · Cited by 730 · see citing works
Endogenous nitrogen oxides and bronchodilator S-nitrosothiols in human airways.
Gaston, B. M., Reilly, J., Drazen, J. M., Fackler, J. C., Ramdev, P., Arnelle, D. R., Mullins, M. E., Sugarbaker, D. J., Chee, C., Singel, D. J., et al. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.23.10957 · Cited by 620 · see citing works
Liu, X., Miller, M. J. S., Joshi, M. S., Thomas, D. D., & Lancaster, J. R. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.5.2175 · Cited by 602 · see citing works
Peroxynitrite reactivity with amino acids and proteins
Alvarez, B., & Radi, R. (2003) · Amino Acids · doi:10.1007/s00726-003-0018-8 · Cited by 560 · see citing works
Rapid reaction between peroxonitrite ion and carbon dioxide: Implications for biological activity
Lymar, S. V., & Hurst, J. K. (1995) · Journal of the American Chemical Society · doi:10.1021/ja00139a027 · Cited by 515 · see citing works
Fritsche, E., Schäfer, C., Calles, C., Bernsmann, T., Bernshausen, T., Wurm, M., Hübenthal, U., Cline, J. E., Hajimiragha, H., Schroeder, P., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0701764104 · Cited by 437 · see citing works
Fürstner, A., Ackermann, L., Gabor, B., Goddard, R., Lehmann, C. W., MYNOTT, R. J., Stelzer, F., & Thiel, O. R. (2001) · Chemistry - A European Journal · doi:10.1002/1521-3765(20010803)7:15 · Cited by 423 · see citing works
NUCLEAR AND MITOCHONDRIAL COMPARTMENTATION OF OXIDATIVE STRESS AND REDOX SIGNALING
Hansen, J. M., Go, Y., & Jones, D. P. (2005) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.46.120604.141122 · Cited by 401 · see citing works
The reaction of NO· with O2·− and HO2·−: A pulse radiolysis study
Goldstein, S., & Czapski, G. (1995) · Free Radical Biology and Medicine · doi:10.1016/0891-5849(95)00034-u · Cited by 398 · see citing works
Prütz, W. A., Mönig, H., Butler, J., & Land, E. J. (1985) · Archives of Biochemistry and Biophysics · doi:10.1016/0003-9861(85)90780-5 · Cited by 338 · see citing works
Kinetics of the Reaction of Nitric Oxide with Oxygen in Aqueous Solutions
Lewis, R. S., & Deen, W. M. (1994) · Chemical Research in Toxicology · doi:10.1021/tx00040a013 · Cited by 293 · see citing works
Self-citationNitric Oxide Induces Oxidative Damage in Addition to Deamination in Macrophage DNA
deRojas-Walker, T., Tamir, S., Ji, H., Wishnok, J. S., & Tannenbaum, S. R. (1995) · Chemical Research in Toxicology · doi:10.1021/tx00045a020 · Cited by 253 · see citing works
Tamir, S., Burney, S., & Tannenbaum, S. R. (1996) · Chemical Research in Toxicology · doi:10.1021/tx9600311 · Cited by 248 · see citing works
Reaction of Superoxide and Nitric Oxide with Peroxynitrite
Jourd’heuil, D., Jourd’heuil, F. L., Kutchukian, P. S., Musah, R. A., Wink, D. A., & Grisham, M. B. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m102341200 · Cited by 239 · see citing works
Ford, E., Hughes, M., & Wardman, P. (2002) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(02)00850-x · Cited by 229 · see citing works
Kinetics and Mechanism of the Reaction of Cysteine and Hydrogen Peroxide in Aqueous Solution
Luo, D., Smith, S. W., & Anderson, B. D. (2004) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.20253 · Cited by 226 · see citing works
Mechanism of Reaction of Myeloperoxidase with Nitrite
Burner, U., Furtmüller, P. G., Kettle, A. J., Koppenol, W. H., & Obinger, C. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m000181200 · Cited by 220 · see citing works
The role of nitric oxide (NO·) in the carcinogenic process
Tamir, S., & Tannenbaum, S. R. (1996) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/0304-419x(96)00021-2 · Cited by 220 · see citing works
Lancaster, J. R. (2006) · Chemical Research in Toxicology · doi:10.1021/tx060061w · Cited by 219 · see citing works
García‐Ruiz, C., Morales, A., Ballesta, A. M., Rodés, J., Kaplowitz, N., & Fernández-Checa, J. C. (1994) · Journal of Clinical Investigation · doi:10.1172/jci117306 · Cited by 218 · see citing works
Carbonate radical in flash photolysis and pulse radiolysis of aqueous carbonate solutions
Béhar, D., Czapski, G., & Duchovny, I. (1970) · The Journal of Physical Chemistry · doi:10.1021/j100909a029 · Cited by 211 · see citing works
Goldstein, S., & Czapski, G. (1996) · Journal of the American Chemical Society · doi:10.1021/ja9536680 · Cited by 205 · see citing works
[3] Kinetic factors that control the fate of thiyl radicals in cells
Wardman, P., & von Sonntag, C. (1995) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/0076-6879(95)51108-3 · Cited by 204 · see citing works
Pulse radiolysis study of sulfhydryl compounds in aqueous solution
Hoffman, M. Z., & Hayon, E. (1973) · The Journal of Physical Chemistry · doi:10.1021/j100627a005 · Cited by 200 · see citing works
Oxidation and Nitrosation of Thiols at Low Micromolar Exposure to Nitric Oxide
Jourd’heuil, D., Jourd’heuil, F. L., & Feelisch, M. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300203200 · Cited by 194 · see citing works
Ascorbic Acid Transport and Accumulation in Human Neutrophils
Washko, P., Rotrosen, D., & Levine, M. (1989) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)47256-6 · Cited by 193 · see citing works
Chen, S., & Hoffman, M. Z. (1973) · Radiation Research · doi:10.2307/3573789 · Cited by 192 · see citing works
Bonini, M. G., & Augusto, O. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m008456200 · Cited by 191 · see citing works
Tyrosine Nitration by Simultaneous Generation of ⋅NO and O⨪2 under Physiological Conditions
Goldstein, S., Czapski, G., Lind, J., & Merényi, G. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.5.3031 · Cited by 177 · see citing works
Kluge, I., Gutteck‐Amsler, U., Zollinger, M., & Kim, Q. (1997) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1997.69062599.x · Cited by 174 · see citing works
Pulsradiolytische Untersuchung einiger Elementarprozesse der Oxydation und Reduktion des Nitritions
Grätzel, M., Henglein, A., Lilie, J., & Beck, G. (1969) · Berichte der Bunsengesellschaft für physikalische Chemie · doi:10.1002/bbpc.19690730707 · Cited by 166 · see citing works
Kinetic Analysis of the Fate of Nitric Oxide Synthesized by Macrophages in Vitro
Lewis, R. S., Tamir, S., Tannenbaum, S. R., & Deen, W. M. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.49.29350 · Cited by 161 · see citing works
Self-citationThe effect of oxygen, antioxidants, and superoxide radical on tyrosine phenoxyl radical dimerization
Hunter, E. P. L., Desrosiers, M. F., & Simic, M. G. (1989) · Free Radical Biology and Medicine · doi:10.1016/0891-5849(89)90064-6 · Cited by 153 · see citing works
Advances in environmental science and technology
Lodge, J. P. (1979) · Atmospheric Environment (1967) · doi:10.1016/0004-6981(79)90211-7 · Cited by 138 · see citing works
S-nitrosation of glutathione by nitric oxide, peroxynitrite, and •NO/O2•−
Schrammel, A. (2003) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(03)00038-8 · Cited by 130 · see citing works
Kinetics of S-nitrosation of thiols in nitric oxide solutions
Keshive, M., Singh, S., Wishnok, J. S., Tannenbaum, S. R., & Deen, W. M. (1996) · Chemical Research in Toxicology · doi:10.1021/tx960036y · Cited by 121 · see citing works
Self-citationZhang, H., Joseph, J., Felix, C. C., & Kalyanaraman, B. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.19.14038 · Cited by 118 · see citing works
Role of the Carbonate Radical Anion in Tyrosine Nitration and Hydroxylation by Peroxynitrite
Santos, C. X. C., Bonini, M. G., & Augusto, O. (2000) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.2000.1751 · Cited by 104 · see citing works
Quijano, C., Romero, N., & Radí, R. (2005) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2005.04.014 · Cited by 102 · see citing works
Membrane “Lens” Effect: Focusing the Formation of Reactive Nitrogen Oxides from the •NO/O2 Reaction
Möller, M. N., Li, Q., Vitturi, D. A., Robinson, J. M., Lancaster, J. R., & Denicola, A. (2007) · Chemical Research in Toxicology · doi:10.1021/tx700010h · Cited by 98 · see citing works
Reactivity of hydroxyl with tyrosine in aqueous solution studied by pulse radiolysis
Solar, S., Solar, W., & Getoff, N. (1984) · The Journal of Physical Chemistry · doi:10.1021/j150654a030 · Cited by 95 · see citing works
The Mechanism of Photochemical Release of Nitric Oxide from S‐Nitrosoglutathione
Wood, P. D., Mutus, B., & Redmond, R. W. (1996) · Photochemistry and Photobiology · doi:10.1111/j.1751-1097.1996.tb03099.x · Cited by 92 · see citing works
Reactivity of Nitric Oxide with Simple Short-Lived Radicals in Aqueous Solutions
Czapski, G., Holcman, J., & Bielski, B. H. J. (1994) · Journal of the American Chemical Society · doi:10.1021/ja00104a028 · Cited by 84 · see citing works
Damage of amino acids and proteins induced by nitrogen dioxide, a free radical toxin, in air
Kikugawa, K., Kato, T., & Okamoto, Y. (1994) · Free Radical Biology and Medicine · doi:10.1016/0891-5849(94)90039-6 · Cited by 83 · see citing works
Jones, C. M., Lawrence, A. D., Wardman, P., & Burkitt, M. J. (2003) · Biochemical Society Transactions · doi:10.1042/bst0311337 · Cited by 80 · see citing works
Dong, M., Wang, C., Deen, W. M., et al. (2003) · Chemical Research in Toxicology · doi:10.1021/tx034046s · Cited by 76 · see citing works
Self-citationRamírez, D. C., Gomez-Mejiba, S., & Mason, R. P. (2004) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2004.10.008 · Cited by 69 · see citing works
Reactivity of Peroxynitrite versus Simultaneous Generation of • NO and O 2 • - toward NADH
Goldstein, S., & Czapski, G. (2000) · Chemical Research in Toxicology · doi:10.1021/tx000099n · Cited by 67 · see citing works
Dong, M., & Dedon, P. C. (2005) · Chemical Research in Toxicology · doi:10.1021/tx050252j · Cited by 60 · see citing works
Self-citationThe Reaction of S-Nitrosoglutathione with Superoxide
Jourd’heuil, D., Mai, C. T., Laroux, F. S., Wink, D. A., & Grisham, M. B. (1998) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1998.8227 · Cited by 56 · see citing works
Goldstein, S., Lind, J. U., & Merényi, G. (2004) · The Journal of Physical Chemistry A · doi:10.1021/jp037431z · Cited by 49 · see citing works
Hodges, G. R., Marwaha, J., Paul, T., & Ingold, K. U. (2000) · Chemical Research in Toxicology · doi:10.1021/tx0001272 · Cited by 43 · see citing works
Evaluation of the “radical sink” hypothesis from a chemical-kinetic viewpoint
Wardman, P. (1998) · Journal of Radioanalytical and Nuclear Chemistry · doi:10.1007/bf02383706 · Cited by 34 · see citing works
Analysis of Cellular Exposure to Peroxynitrite in Suspension Cultures
Nalwaya, N., & Deen, W. M. (2003) · Chemical Research in Toxicology · doi:10.1021/tx025664w · Cited by 32 · see citing works
Self-citationMicroscopic modeling of NO andS-nitrosoglutathione kinetics and transport in human airways
Shin, H., & George, S. C. (2001) · Journal of Applied Physiology · doi:10.1152/jappl.2001.90.3.777 · Cited by 28 · see citing works
Karunakaran, C., Zhang, H., Joseph, J., et al. (2005) · Chemical Research in Toxicology · doi:10.1021/tx049747j · Cited by 26 · see citing works
Biological role of glutathione in nitric oxide-induced toxicity in cell culture and animal models
Li, C., Wright, T. L., Dong, M., Dommels, Y. E. M., Trudel, L. J., Dedon, P. C., Tannenbaum, S. R., & Wogan, G. N. (2005) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2005.07.011 · Cited by 21 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Glutathione Homeostasis and Functions: Potential Targets for Medical Interventions
Lushchak, V. I. (2012) · Journal of Amino Acids · doi:10.1155/2012/736837 · Cited by 1,266 · see citing works
Chemical biology of peroxynitrite: Kinetics, diffusion, and radicals
Ferrer-Sueta, G., & Radi, R. (2009) · ACS Chemical Biology · doi:10.1021/cb800279q · Cited by 776 · see citing works
Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation
Tejero, J., Shiva, S., & Gladwin, M. T. (2019) · Physiological Reviews · doi:10.1152/physrev.00036.2017 · Cited by 541 · see citing works
Glutathione Peroxidase-3 Deficiency Promotes Platelet-Dependent Thrombosis In Vivo
Jin, R. C., Mahoney, C. E., (Coleman) Anderson, L., Ottaviano, F., Croce, K., Leopold, J. A., Zhang, Y.-Y., Tang, S.-S., Handy, D. E., & Loscalzo, J. (2011) · Circulation · doi:10.1161/circulationaha.110.000034 · Cited by 186 · see citing works
One- and two-electron oxidation of thiols: mechanisms, kinetics and biological fates
Trujillo, M., Alvarez, B., & Radi, R. (2016) · Free Radical Research · doi:10.3109/10715762.2015.1089988 · Cited by 142 · see citing works
Wolhuter, K., Whitwell, H. J., Switzer, C. H., Burgoyne, J. R., Timms, J. F., & Eaton, P. (2018) · Molecular Cell · doi:10.1016/j.molcel.2017.12.019 · Cited by 111 · see citing works
How widespread is stable protein S-nitrosylation as an end-effector of protein regulation?
Wolhuter, K., & Eaton, P. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.02.013 · Cited by 55 · see citing works
Bruegger, J. J., Smith, B. C., Wynia-Smith, S. L., & Marletta, M. A. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.m117.817700 · Cited by 27 · see citing works
- Authors
- Lim, C. H., Dedon, P. C., & Deen, W. M.
- Affiliations
- Massachusetts Institute of Technology (US)
- Corresponding author
- Deen, William M.
- Venue
- Chemical Research in Toxicology
- Publisher
- American Chemical Society (ACS)
- Published
- 2008-10-02
- Volume
- 21
- Issue
- 11
- Pages
- 2134-2147
- ISSN
- 0893-228X (ISSN-L)
- 1520-5010
- PMC
- PMC3722615
- OpenAlex
- W2089995708
- Cited by
- 93
- References
- 65
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 3 · 2023: 7 · 2022: 2 · 2021: 1 · 2020: 7 · 2019: 8 · 2018: 5 · 2017: 5 · 2016: 6 · 2015: 6 · 2014: 4 · 2013: 7 · 2012: 9
- FWCI
- 2.47
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Chemical Research in Toxicology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P01-CA 26731, P01CA026731)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- reactive nitrogen species, nitric oxide, peroxynitrite, nitrite, nitrous oxide, glutathione, vitamin C, S-nitrosoglutathione, nitrotyrosine, kinetic modeling, inflamed tissue, lipid oxidation, free radical scavenging
- MeSH terms
- Glutathione, Kinetics, Models, Biological, Nitric Oxide, Tyrosine, Hydroxyl Radical, Reactive Nitrogen Species, S-Nitrosoglutathione
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
