Nitrotyrosine Explained

Nitrotyrosine is a product of tyrosine nitration mediated by reactive nitrogen species such as peroxynitrite anion and nitrogen dioxide. Nitrotyrosine is identified as an indicator or marker of cell damage, inflammation as well as NO (nitric oxide) production. Nitrotyrosine is formed in the presence of the active metabolite NO. Generally in many disease states, oxidative stress increases the production of superoxide (O₂⁻) and NO forming peroxynitrite (ONOO⁻) a destructive free radical oxidant.^[1] The production of ONOO⁻ is capable of oxidizing several lipoproteins and of nitrating tyrosine residues in many proteins. It is difficult to determine the production of ONOO⁻ so, usually nitrotyrosine in proteins are the detectable marker for indirectly detecting ONOO⁻. It is detected in large number of pathological conditions^{[2] [3]} and is considered a marker of NO-dependent, reactive nitrogen species-induced nitrative stress. Nitrotyrosine is detected in biological fluids such as plasma, lung aspirants-BALF (Broncho alveolar lining fluid) and urine. Increased level of nitrotyrosine is detected in rheumatoid arthritis,^[4] septic shock^[5] and coeliac disease.^[6] In all these studies nitrotyrosine was undetected in healthy subjects. Nitrotyrosine is also found in numerous other disease-affected tissues, such as the cornea in keratoconus.^[7] Peroxynitrite and/or nitrative stress may participate in the pathogenesis of diabetes.^{[3] [8]}

Research shows that nitrotyrosine levels can be reduced by N-acetyl cysteine,^{[9] [10]} which is a precursor to glutathione, one of the body's primary endogenous antioxidants. Nitrotyrosine levels have been linked to cerebral ischemia and edema, for which NAC has also been proven as a potential treatment.^[11]

Free nitrotyrosine undergoes metabolism to form 3-nitro-4-hydroxyphenylacetic acid (NHPA) which is excreted in the urine.^{[12] [13]}

Nitrotyrosine, as a marker of reactive oxygen species, has also been linked to degeneration of dopamine neurons.^[14] Tyrosine is the precursor to dopamine, a neurotransmitter that's important for motivation, attention, learning, circadian rhythms, and other biological processes.

Notes and References

1. Ischiropoulos H. Biological Tyrosine Nitration: A Pathophysiological Function of Nitric Oxide and Reactive Oxygen Species. Archives of Biochemistry and Biophysics. Elsevier Science. 356. 1. 1–11. August 1998. 9681984. 10.1006/abbi.1998.0755. free.
2. Mohiuddin I, Chai H, Lin PH, Lumsden AB, Yao Q, Chen C. Nitrotyrosine and Chlorotyrosine: Clinical Significance and Biological Functions in the Vascular System. Elsevier

   Association for Academic Surgery

   . . 133. 2. 143–149. June 2006. 10.1016/j.jss.2005.10.008 . 16360172.
3. Pacher P, Beckman JS, Liaudet L. Nitric Oxide and Peroxynitrite in Health and Disease . Physiological Reviews. American Physiological Society. 87. 1. 315–424. 1 January 2007. 17237348 . 2248324. 10.1152/physrev.00029.2006. free.
4. Kaur H, Halliwell B. 1994. 350. 1. FEBS Letters. Wiley Publishing. 10.1016/0014-5793(94)00722-5 . 8062931. Evidence for nitric oxide-mediated oxidative damage in chronic inflammation Nitrotyrosine in serum and synovial fluid from rheumatoid patients. 9–12.
5. Fukuyama N, Takebayashi Y, Hida M, Ishida H, Ichimori K, Nakazawa H. Clinical evidence of peroxynitrite formation in chronic renal failure patients with septic shock. Free Radical Biology & Medicine . Elsevier Science. 22. 5 . 771–774. 1997. 9119244. 10.1016/S0891-5849(96)00401-7.
6. ter Steege JC, Koster-Kamphuis L, van Straaten EA, Forget PP, Buurman WA . Nitrotyrosine in plasma of celiac disease patients as detected by a new sandwich ELISA . Free Radical Biology & Medicine . 25 . 8 . 953–963 . November 1998 . 9840741 . 10.1016/s0891-5849(98)00184-1.
7. Buddi R, Lin B, Atilano SR, Zorapapel NC, Kenney MC, Brown DJ . Evidence of oxidative stress in human corneal diseases . The Journal of Histochemistry and Cytochemistry . 50 . 3 . 341–351 . March 2002 . 11850437 . 10.1177/002215540205000306 . free.
8. Pacher P, Obrosova IG, Mabley JG, Szabó C . Role of nitrosative stress and peroxynitrite in the pathogenesis of diabetic complications. Emerging new therapeutical strategies . Current Medicinal Chemistry . 12 . 3 . 267–275 . 2005 . 15723618 . 2225483 . 10.2174/0929867053363207.
9. Ivanovski O, Szumilak D, Nguyen-Khoa T, Ruellan N, Phan O, Lacour B, Descamps-Latscha B, Drüeke TB, Massy ZA . The antioxidant N-acetylcysteine prevents accelerated atherosclerosis in uremic apolipoprotein E knockout mice . Kidney International . 67 . 6 . 2288–2294 . June 2005 . 15882270 . 10.1111/j.1523-1755.2005.00332.x . free.
10. Mani AR, Ippolito S, Ollosson R, Moore KP . Nitration of cardiac proteins is associated with abnormal cardiac chronotropic responses in rats with biliary cirrhosis . Hepatology . 43 . 4 . 847–856 . April 2006 . 16557556 . 10.1002/hep.21115 . 24189201. free .
11. Cuzzocrea S, Mazzon E, Costantino G, Serraino I, Dugo L, Calabrò G, Cucinotta G, De Sarro A, Caputi AP . Beneficial effects of n-acetylcysteine on ischaemic brain injury . British Journal of Pharmacology . 130 . 6 . 1219–1226 . July 2000 . 10903958 . 1572181 . 10.1038/sj.bjp.0703421.
12. Ohshima H, Friesen M, Brouet I, Bartsch H . Nitrotyrosine as a new marker for endogenous nitrosation and nitration of proteins . Food and Chemical Toxicology . 28 . 9 . 647–652 . September 1990 . 2272563 . 10.1016/0278-6915(90)90173-k .
13. Mani AR, Pannala AS, Orie NN, Ollosson R, Harry D, Rice-Evans CA, Moore KP . Nitration of endogenous para-hydroxyphenylacetic acid and the metabolism of nitrotyrosine . The Biochemical Journal . 374 . Pt 2 . 521–527 . September 2003 . 12797864 . 10.1042/bj20030670 . 1223612.
14. Kuhn DM, Sakowski SA, Sadidi M, Geddes TJ . Nitrotyrosine as a marker for peroxynitrite-induced neurotoxicity: The beginning or the end of the end of dopamine neurons? . Journal of Neurochemistry . 89 . 3 . 529–536 . 2004 . 15086510 . 10.1111/j.1471-4159.2004.02346.x . free .