F2‐Isoprostanes as Markers of Oxidant Stress: An Overview

Erik S. Musiek1, Jason D. Morrow1

1 Vanderbilt University School of Medicine, Nashville, Tennessee
Publication Name:  Current Protocols in Toxicology
Unit Number:  Unit 17.5
DOI:  10.1002/0471140856.tx1705s24
Online Posting Date:  June, 2005
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Abstract

The isoprostanes are a unique series of prostaglandin‐like compounds formed in vivo via a non‐enzymatic mechanism involving the free radical–initiated peroxidation of arachidonic acid. This unit summarizes selected aspects regarding current knowledge of these compounds and their value as markers of oxidative injury. Novel aspects related to the biochemistry of isoprostane formation are discussed and methods by which these compounds can be analyzed and quantified are summarized. A considerable portion of this unit examines the utility of F2‐isoprostanes as markers of oxidant injury in vitro and in vivo. Numerous studies carried out over the past decade have shown that these compounds are extremely accurate measures of lipid peroxidation in animals and humans and have illuminated the role of oxidant injury in a number of human diseases.

Keywords: lipid peroxidation; eicosanoid; isoprostane; lipid; oxidative stress

     
 
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Table of Contents

  • Mechanism of Formation of Isoprostanes
  • Quantification of F2‐Isoprostanes
  • F2‐Isoprostanes as an Index of Oxidant Stress
  • F2‐Isoprostane Formation in Human Diseases
  • Conclusions
  • Literature Cited
  • Figures
  • Tables
     
 
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Materials

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Literature Cited

Literature Cited
   Aleynik, S.I., Leo, M.A., Aleynik, M.K., and Lieber, C.S. 1999. Increased circulating products of lipid peroxidation in patients with alcoholic liver disease. Alcohol Clin. Exp. Res. 22:192‐196.
   Awad, J.A., Morrow, J.D., Hill, K.E., Roberts, L.J., and Burk, R.F. 1994. Detection and localization of lipid peroxidation in selenium‐ and vitamin‐E deficient rats using F2‐isoprostanes, J. Nutr. 124:810‐816.
   Basu, S., Whiteman, M., Mattey, D.L., and Halliwell, B. 2001. Raised levels of F(2)‐isoprostanes and prostaglandin F(2alpha) in different rheumatic diseases. Ann. Rheum. Dis. 60:627‐631.
   Bohnstedt, K.C., Karlberg, B., Wahlund, L.O., Jonhagen, M.E., Basun, H., and Schmidt, S. 2003. Determination of isoprostanes in urine samples from Alzheimer patients using porous graphitic carbon liquid chromatography‐tandem mass spectrometry. J. Chromatogr. B. 796:11‐19.
   Boushey, C.J., Beresford, S.A., Omenn, G.S., and Motulsky, A.G. 1995. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. J. Am. Med. Assoc. 274:1049‐1057.
   Burk, R.F., Hill, K.E., Awad, J.A., Morrow, J.D., Kato, T., Cockell, K.A., and Lyons, P.R. 1995. Pathogenesis of diquat‐induced liver necrosis in selenium‐deficient rats: Assessment of the roles of lipid peroxidation and selenoprotein P. Hepatology 21:561‐569.
   Carpenter, C.T., Price, P.V., and Christman, B.W. 1998. Exhaled breath condensate isoprostanes are elevated in patients with acute lung injury or ARDS. Chest 114:1653‐1659.
   Chen, Y., Morrow, J.D., and Roberts, L.J. 2nd 1999. Formation of reactive cyclopentenone compounds in vivo as products of the isoprostane pathway. J. Biol. Chem. 274:10863‐10868.
   Cracowski, J.L., Cracowski, C., Bessard, G., Pepin, J.L., Bessard, J., Schwebel, C., Stanke‐Labesque, F., and Pison, C. 2001. Increased lipid peroxidation in patients with pulmonary hypertension. Am. J. Resp. Crit. Care Med. 164:1038‐1042.
   Davi, G., Alessandrini, P, Mezzetti, A., Minotti, G., Bucciarelli, T., Costantini, F., Cipollone, F., Bon, G.B., Ciabattoni, G., and Patrono, C. 1997. In vivo formation of 8‐Epi‐prostaglandin F2 alpha is increased in hypercholesterolemia. Atheroscler. Thromb. Vasc. Biol. 117:3230‐3235.
   Davi, G., Ciabattoni, G., Consoli, A., Mezzetti, A., Falco, A., Santarone, S., Pennese, E., Vitacolonna, E., Bucciarelli, T., Costantini, F., Capani, F., and Patrono, C. 1999. In vivo formation of 8‐iso‐prostaglandin F2alpha and platelet activation in diabetes mellitus: Effects of improved metabolic control and vitamin E supplementation. Circulation 99:224‐229.
   Dworski, R., Murray, J.J., Roberts, L.J., Oates, J.A., Morrow, J.D., Fisher, L., and Sheller, J.R. 1999. Allergen‐induced synthesis of F(2)‐isoprostanes in atopic asthmatics. Evidence for oxidant stress. Am. J. Respir. Crit. Care Med. 160:1947‐1951.
   Ekmekcioglu, C., Schweiger, B., Strauss‐Blasche, G., Mundigler, G., Siostrzonek, P., and Marktl, W. 2002. Urinary excretion of 8‐iso‐PGF(2 alpha) in three patients during sepsis, recovery and state of health. Prostaglandins, Leukot. Essent. Fatty Acids 66:441‐442.
   Fam, S.S. and Morrow, J.D. 2003. The isoprostanes: Unique products of arachidonic acid oxidation—A review. Curr. Med. Chem. 10:1723‐1740.
   Feillet‐Coudray, C., Tourtauchaux, R., Niculescu, N., Rock, E., Tauveron, I., Alexandre‐Gouabau, M., Rayssiguier, R., Jalenques, Y.I., and Mazur, A. 1999. Plasma levels of 8‐epi‐PGF2α, an in vivo marker of oxidative stress, are not affected by aging or Alzheimer's disease. Free Rad. Biol. Med. 27:463‐469.
   Frei, B., Forte, T.M., Ames, B.N., and Cross, C.E. 1991. Gas phase oxidants of cigarette smoke induce lipid peroxidation and changes in lipoprotein properties in human blood plasma. Protective effects of ascorbic acid. Biochem. J. 277:133‐138.
   Gniwotta, C., Morrow, J.D., Roberts, L.J., and Kuhn, H. 1997. Prostaglandin F2‐like compounds, F2‐isoprostanes, are present in increased amounts in human atherosclerotic lesions. Arterioscler. Thromb. Vasc. Biol. 17:3236‐3241.
   Gopaul, N.K., Nourooz‐Zadeh, J., Malle, A.I., and Anggard, E.E. 1994. Formation of F2‐isoprostanes during aortic endothelial cell‐mediated oxidation of low density lipoprotein. FEBS Lett. 348:297‐300.
   Gopaul, N.K., Anggard, E.E., Mallet, A.I., Beteridge, D.J., Wolff, S.P., and Nourooz‐Zadey, J. 1995. Plasma 8‐epi‐PGF2 alpha levels are elevated in individuals with non‐insulin dependent diabetes mellitus. FEBS Lett. 368:225‐229.
   Halliwell, B. and Grootveld, M. 1987. The measurement of free radical reactions in humans. FEBS Lett. 213:9‐14.
   Holt, S., Reeder, B., Wilson, M., Harvey, S., Morrow, J.D., Roberts, L.J. II, and Moore, K. 1999. Increased lipid peroxidation in patients with rhabdomyolysis. Lancet 353:1241.
   Kannel, W.B. 1981. Update on the role of cigarette smoking in coronary artery disease. Am. Heart J. 101:319‐328.
   Klings, E.S., Christman, B.W., McClung, J., Stucchi, A.F., McMahon, L., Brauer, M., and Farber, H.W. 2001. Increased F2 isoprostanes in the acute chest syndrome of sickle cell disease as a marker of oxidative stress. Am. J. Resp. Crit. Care Med. 164:1248‐1252.
   Leo, M.A., Aleynik, S.I., Siegel, J.H., Kasmin, F.E., Aleynik, M.K., and Lieber, C.S. 1997. F2‐isoprostane and 4‐hydroxynonenal excretion in human bile of patients with biliary tract and pancreatic disorders. Am. J. Gastroenterol. 92:2069‐2072.
   Liang, Y., Wei, P., Duke, R.W., Reaven, P.D., Harman, S.M., Cutler, R.G., and Heward, C.B. 2000. Quantification of 8‐iso‐prostaglandin‐F(2alpha) and 2,3‐dinor‐8‐iso‐prostaglandin‐F(2alpha) in human urine using liquid chromatography‐tandem mass spectrometry. Free Radic. Biol. Med. 34:409‐418.
   Liu, T., Stern, A., Roberts, L.J., and Morrow, J.D. 1999. The isoprostanes: Novel prostaglandin‐like products of the free radical‐catalyzed peroxidation of arachidonic acid. J. Biomed. Sci. 6:226‐235.
   Longmire, A.W., Swift, L.L., Roberts, L.J., Awad, J.A., Burk, R.F., and Morrow, J.D. 1994. Effect of oxygen tension on the generation of F2‐isoprostanes and malondialdehyde in peroxidizing rat liver microsomes. Biochem. Pharm. 47:1173‐1177.
   Lynch, S.M., Morrow, J.D., Roberts, L.J., and Frei, B. 1994. Formation of non‐cyclooxygenase‐derived prostanoids (F2‐isoprostanes) in plasma and low density lipoprotein exposed to oxidative stress in vitro. J. Clin. Invest. 93:998‐1004.
   Marin, J.G., Cornet, S., Spinnewyn, B., Demerle‐Pallardy, C., Auguet, M., and Chabrier, P.E. 2000. BN 80933 inhibits F2‐isoprostane elevation in focal cerebral ischaemia and hypoxic neuronal cultures. Neuroreport. 11:1357‐1360.
   Markesbery, W.R. 1997. Oxidative stress hypothesis in Alzheimer's disease. Free Rad. Biol. Med. 23:137‐147.
   Montine, T.J., Markesbery, W.R., Morrow, J.D., and Roberts, L.J. 1998. Cerebrospinal fluid F2‐isoprostane levels are increased in Alzheimer's disease. Ann. Neurol. 44:410‐413.
   Montine, T.J., Markesbery, W.R., Zackert, W., Sanchez, S.C., Roberts, L.J. 2nd, and Morrow, J.D. 1999a. The magnitude of brain lipid peroxidation correlates with the extent of degeneration but not with density of neuritic plaques or neurofibrillary tangles or with APOE genotype in Alzheimer's disease patients. Am. J. Pathol. 155:863‐868.
   Montine, T.J., Beal, M.F., Cudkowicz, M.E., O'Donnell, H., Margolin, R.A., McFarland, L., Bachrach, A.F., Zackert, W.E., Roberts, L.J., and Morrow, J.D. 1999b. Increased CSF F2‐isoprostane concentration in probable AD. Neurology. 52:562.
   Montine, T.J., Beal, M.F., Robertson, D., Cudkowicz, M.E., Biaggioni, I., Brown, R.H., O'Donnel, H., Zackert, W.E., Roberts, L.J., and Morrow, J.D. 1999c. Cerebrospinal fluid F2‐isoprostanes are elevated in Huntington's disease. Neurology 52:1104‐1105.
   Montine, T.J., Milatovic, D., Gupta, R.C., Valyi‐Nagy, T., Morrow, J.D., and Breyer, R.M. 2002a. Neuronal oxidative damage from activated innate immunity is EP2 receptor‐dependent. J. Neurochem. 83:463‐470.
   Montine, T.J., Quinn, J.F., Milatovic, D., Silbert, L.C., Dang, T., Sanchez, S., Terry, E., Roberts, L.J. 2nd, Kaye, J.A., and Morrow, J.D. 2002b. Peripheral F2‐isoprostanes and F4‐neuroprostanes are not increased in Alzheimer's disease. Ann. Neurol. 52:175‐179.
   Montuschi, P., Ciabattoni, G., Paredi, P., Pantelidis, P., DuBois, R.M., Kharitoniv, S.A., and Barnes, P.J. 1998. 8‐Isoprostane as a biomarker of oxidative stress in interstitial lung diseases. Am. J. Resp. Crit. Care Med. 158:1524‐1527.
   Morales, C.R., Terry, E.S., Zackert, W.E., Montine, T.J., and Morrow, J.D. 2001. Improved assay for the quantification of the isoprostane 15‐F2t‐isoprostane (8‐iso‐PGF2α) by a stable isotope dilution mass spectrometric assay. Clin. Chim. Acta 314:93‐99.
   Morrow, J.D. and Roberts, L.J. 1997. The isoprostanes: Unique bioactive products of lipid peroxidation. Prog. Lipid Res. 36:1‐21.
   Morrow, J.D. and Roberts, L.J. 1999. Mass spectrometric quantification of F2‐isoprostanes in biological fluids and tissues as measure of oxidant stress. Meth. Enzymol. 300:3‐12.
   Morrow, J.D., Hill, K.E., Burk, R.F., Nammour, T.M., Badr, K.F., and Roberts, L.J. 1990a. A series of prostaglandin F2‐like compounds are produced in vivo in humans by a non‐cyclooxygenase, free radical‐catalyzed mechanism. Proc. Natl. Acad. Sci. U.S.A. 87:9383‐9397.
   Morrow, J.D., Harris, T.M., and Roberts, L.J. 1990b. Noncyclooxygenase oxidative formation of a series of novel prostaglandins: Analytical ramifications for measurement of eicosanoids. Analyt. Biochem. 184:1‐10.
   Morrow, J.D., Awad, J.A., Kato, T., Takahashi, K., Badr, K.F., Roberts, L.J., and Burk, R.F. 1992. Formation of novel non‐cyclooxygenase‐derived prostanoids (F2‐isoprostanes) in carbon tetrachloride hepatotoxicity. J. Clin. Invest. 90:2502‐2507.
   Morrow, J.D., Moore, K.P., Awad, J.A., Ravenscraft, M.D., Marini, G., Badr, K.F., Williams R., and Roberts, L.J. 1993. Marked overproduction of non‐cyclooxygenase derived prostanoids (F2‐isoprostanes) in the hepatorenal syndrome. J. Lipid Mediators 6:417‐420.
   Morrow, J.D, Frei, B., Longmire, A.W., Gaziano, M., Lynch, S.M., Shyr, Y., Strauss, W.E., Oates, J.A., and Roberts, L.J. 1995. Increase in circulating products of lipid peroxidation (F2‐isoprostanes) in smokers. Smoking as a cause of oxidative damage. N. Engl. J. Med. 332:1198‐1203.
   Morrow, J.D., Chen, Y., Brame, C.J., Yang, J., Sanchez, S.C., Xu, J., Zackert, W.E., Awad, J.A., and Roberts, L.J. 1999a. The isoprostanes: Unique prostaglandin‐like products of free radical‐initiated lipid peroxidation. Drug Metab. Rev. 31:117‐139.
   Morrow, J.D., Zackert, W.E., Yang, J.P., Kurhts, E.H., Callawaert, D., Dworski, R., Kanai, K., Taber, D., Moore, K., Oates, J.A., and Roberts, L.J. 1999b. Quantification of the major urinary metabolite of 15‐F2t‐isoprostane (8‐iso‐PGF2α) by a stable isotope dilution mass spectrometric assay. Analyt. Biochem. 269:326‐331.
   Natarajan, R., Lanting, L., Gonzales, N., and Nadler, J. 1996. Formation of an F2‐isoprostane in vascular smooth muscle cells by elevated glucose and growth factors. Am. J. Physiol. 271:H159‐165.
   Patel, M., Liang, L.P., and Roberts, L.J. 2nd. 2001. Enhanced hippocampal F2‐isoprostane formation following kainate‐induced seizures. J. Neurochem. 79:1065‐1069.
   Pratico, D. and FitzGerald, G.A. 1996. Generation of 8‐epi‐prostaglandin F2α by human monocytes. Discriminate production by reactive oxygen species and prostaglandin endoperoxide synthase‐2. J. Biol. Chem. 271:8919‐8924.
   Pratico, D., Iuliano, L., Mauriello, A., Spagnoli, L., Lawson, J.A., Rokach, J., Maclouf, J., Violi, F., and FitzGerald, G.A. 1997. Localization of distinct F2‐isoprostanes in human atherosclerotic lesions. J. Clin. Invest. 100:2028‐2034.
   Pratico, D., Barry, O.P., Lawson, J.A., Adiyaman, M., Hwang, S.W., Khanapure, S.P., Iuliano, L., Rokach, J., and FitzGerald, G.A. 1998a. IPF2alpha‐I: An index of lipid peroxidation in humans. Proc. Natl. Acad. Sci U.S.A. 95:3449‐3454.
   Pratico, D., Tangirala, R.K., Rader, D.J., Rokach, J., and FitzGerald, G.A. 1998b. Vitamin E suppresses isoprostane generation in vivo and reduces atherosclerosis in ApoE‐deficient mice. Nat. Med. 4:1189‐1192.
   Pratico, D., Basili, S., Vieri, M., Cordova, C., Violi, V., and FitzGerald, G.A. 1999. Chronic obstructive pulmonary disease is associated with an increase in urinary levels of isoprostane F2alpha‐III, an index of oxidant stress. Am. J. Resp. Crit. Care Med. 158:1709‐1714.
   Pratico, D., Clark, C.M., Lee, V.M., Trojanowski, J.Q., Rokach, J., and FitzGerald, G.A. 2000. Increased 8,12‐iso‐iPF2alpha‐VI in Alzheimer's disease: Correlation of a noninvasive index of lipid peroxidation with disease severity. Ann. Neurol. 48:809‐812.
   Pratico, D., Uryu, K., Leight, S., Trojanoswki, J.Q., and Lee, V.M. 2001. Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J. Neurosci. 21:4183‐4187.
   Pratico, D., Clark, C.M., Liun, F., Rokach, J., Lee, V.Y., and Trojanowski, J.Q. 2002. Increase of brain oxidative stress in mild cognitive impairment: A possible predictor of Alzheimer disease. Arch. Neurol. 59:972‐976.
   Reich, E.E., Markesbery, W.R., Roberts, L.J. 2nd, Swift, L.L., Morrow, J.D., and Montine, T.J. 2001a. Brain regional quantification of F‐ring and D‐/E‐ring isoprostanes and neuroprostanes in Alzheimer's disease. Am. J. Pathol. 158:293‐297.
   Reich, E.E., Markesbery, W.R., Roberts, L.J., Zackert, W.E., Swift, L.L., Morrow, J.D, and Montine, T.J. 2001b. Quantification of F‐ring and D‐/E‐ring isoprostanes and neuroprostanes in Alzheimer's disease. Adv. Exp. Med. Biol. 500:253‐256.
   Reilly, M., Delanty, N., Lawson, J.A., and FitzGerald, G.A. 1996. Modulation of oxidant stress in vivo in chronic cigarette smokers. Circulation 94:19‐25.
   Reilly, M.P., Delanty, M., Roy, L., Rokach, J., Callaghan, P.O., Crean, P., Lawson, J.A., and FitzGerald, G.A. 1997. Increased formation of the isoprostanes IPF2alpha‐I and 8‐epi‐prostaglandin F2alpha in acute coronary angioplasty: Evidence for oxidant stress during coronary reperfusion in humans. Circulation 96:3314‐3320.
   Roberts, L.J. and Morrow, J.D. 1999. Isoprostanes as markers of lipid peroxidation in atherosclerosis. In Molecular and Cellular Basis of Inflammation. (C.N. Serhan and P.A. Ward, eds.) pp. 141. Humana Press, Totowa, N.J.
   Roberts, L.J. II and Morrow, J.D. 2000. Measurement of F2‐Isoprostanes as an index of oxidative stress in vivo. Free Radic. Biol. Med. 28:505‐513.
   Roberts, L.J. and Reckelhoff, J.F. 2001. Measurement of F(2)‐isoprostanes unveils profound oxidative stress in aged rats. Biochem. Biophys. Res. Commun. 287:254‐256.
   Roberts, L.J., Moore, K.P., Zackert, W.E., Oates, J.A., and Morrow, J.D. 1996. Identification of the major urinary metabolite of the F2‐isoprostane 8‐iso‐prostaglandin F2α in humans. J. Biol. Chem. 271:20617‐20620.
   Rokach, J., Khanapure, S.P., Hwang, S.‐W., Adiyaman, M., Lawson, J.A., and FitzGerald, G.A. 1997. The isoprostanes: A perspective. Prostaglandins 54:823‐851.
   Sampson, M.J., Gopaul, N., Davies, I.R., Hughes, D.A., and Carrier, M.J. 2002. Plasma F2 isoprostanes: Direct evidence of increased free radical damage during acute hyperglycemia in type 2 diabetes. Diabetes Care 25:537‐541.
   Sinzinger, H., Lupatelli, G., Chehne, F., Oguogho, A., and Furberg, C.D. 2001. Isoprostane 8‐epi‐PGF2alpha is frequently increased in patients with muscle pain and/or CK‐elevation after HMG‐Co‐enzyme‐A‐reductase inhibitor therapy. J. Clin. Pharm. Ther. 26:303‐310.
   Spittle, M.A., Hoenich, N.A., Handelman, G.J., Adhikarla, R., Homel, P., and Levin, N.W. 2001. Oxidative stress and inflammation in hemodialysis patients. Am. J. Kidney Dis. 38:1408‐1413.
   Stein, C.M., Tanner, S.B., Awad, J.A., Roberts, L.J. II, and Morrow, J.D. 1996. Evidence of free radical‐mediated injury (isoprostane overproduction) in scleroderma. Arth. Rheum. 39:1146‐1150.
   Steinberg, D., Parthasarathy, S., Carew, T.E., Khoo, J.C., and Witztum, J.L. 1989. Beyond cholesterol: Modifications of low density lipoprotein that increase its atherogenicity. N. Engl. J. Med. 86:915‐924.
   Taber, D.F., Morrow, J.D., and Roberts, L.J. 1997. A nomenclature system for the isoprostanes. Prostaglandins 53:63‐67.
   Voutilainen, S., Morrow, J.D., Roberts, L.J., Alfthan, G., Alho, H., Nyyssonen, K., and Salonen, J.T. 1999. Enhanced in vivo lipid peroxidation at elevated plasma total homocysteine levels. Arterioscler. Thromb. Vasc. Biol. 19:1263‐1266.
   Wendland, B.E., Aghdassi, E., Tam, C., Carrier, J., Steinhart, A.H., Wolman, S.L., Baron, D., and Allard, J.P. 2001. Lipid peroxidation and plasma antioxidant micronutrients in Crohn disease. Am. J. Clin. Nutr. 74:259‐264.
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