Review of Concepts and Controversies of Uric Acid as Antioxidant and Pro-Oxidant

Yıl 2015, , 19 - 40, 17.11.2014

Amar Nagesh Kumar Pathiputhuru Aruna Jupalle Nagaiah Naidu Robby Kumar Anuj Kumar Srivastava

https://doi.org/10.17827/aktd.53469

Cited By: 7

Öz

Uric acid, the end product of purine catabolism in humans and is known for its crystal deposition at
higher concentrations (>7 mg/dl) in gout. Less is known about its antioxidant property and the
beneficial effects in various diseases. It is thought that high concentration of uric acid in humans is an
evolutionary advantage and it is also hypothesized that high concentration of uric acid is to
compensate the antioxidant capacity of ascorbic acid which is lost in humans during the course of
evolution. In the extracelluar environment, uric acid can scavenge free radicals like hydroxyl radical,
singlet oxygen and peroxynitrite radical therefore, it is considered as a powerful antioxidant. On the
other hand uric acid depending upon the chemical milieu, changing its property and at times it acts as
pro oxidant and is associated with the pathobiochemistry in developing various diseases like
hypertension, cardio vascular diseases, ischemia reperfusion injury, diabetes mellitus, non alcoholic
fatty liver disorders etc. In this review, we tried to summarize the evolutionary advantages of
hyperuricaemia, effects of both antioxidant property and pro-oxidant nature of uric acid in various
disease conditions.

Anahtar Kelimeler

Hyperuricaemia, antioxidant, pro-oxidant, paradox, beneficial effects of uric acid

Ürik Asidin Antioksidan ve Pro-Oksidan Özellikleri ile İlgili Kavram ve Tartışmalarının Derlemesi

Öz

Ürik asit, insanlarda pürin metabolizmasının son ürünüdür, gutta kristallerinin yoğun olarak (>7 mg/dl) biriktiği bilinmektedir. İnsanlarda, yüksek konsantrasyonda ürik asitin evrimsel bir avantaj 
olduğu düşünülmektedir.Aynı zamanda, insanlarda yüksek ürik asit konsantrasyonunun; evrim 
sürecinde kaybolan askorbik asitin antioksidan kapasitesini telafi ettiği hipotezi ortaya atılmıştır. Hücre 
dışı ortamda, ürik asit; hidroksil, peroksinitrit ve tekil oksijen gibi serbest radikalleri 
uzaklaştırabilmektedir bu sebeple ürik asit güçlü bir antioksidan olarak düşünülmektedir. Öte yandan 
kimyasal ortamına bağlı olarak değişen özelliği ileürik asit, zaman zaman pro-oksidan gibi davranır ve
hipertansiyon, kalp damar hastalıkları, iskemi reperfüzyon hasarı, diyabet, ve alkolsüz yağlı karaciğer 
bozuklukları gibi çeşitli hastalıkların patokimyası ile ilişkilidir. Bu çalışmamızda, hiperüreseminin 
evrimsel avantajlarını ve çeşitli hastalık koşullarında, ürik asitin hem antioksidan özelliğinin hem de 
pro-oksidan doğasının etkilerini özetlemeyeçalıştık.

Anahtar Kelimeler

Hiperüresemi, antioksidan, pro-oksidan, paradoks, ürik astin faydalı etkileri

Kaynakça

• Oda M, Satta Y, Takenaka O, Takahata N. Loss of urate oxidase activity in hominoids and its evolutionary implications. Mol Biol Evol. 2002;19:640–53.
• Jin M, Yang F, Yang I, Yin Y, Luo JJ, Wang H, Yang X F. Uric acid, hyperuricemia and vascular diseases. Front Biosci. 2012;17:656–69.
• Lario BA, Vicente JM. Uric acid and evolution. Rheumatology. 2010;49:2010-15.
• Wu X, Muzny DM, Lee CC, Caskey CT. Two independent mutational events in the loss of urate oxidase during hominoid evolution. J Mol Evol. 1992;34:78–84.
• Jhonson RJ, Titte S, Cade JR, Rideout BA, Oliver WJ. Uric acid, evolution and primitive cultures. Semin Nephrol. 2005;25:3–8.
• Hayashi S, Fujiwara S, Noguchi T. Evolution of urate-degrading enzymes in animal peroxisomes. Cell Biochem Biophys. 2000;32:123–9.
• Kutzing MK, Firestein BL. Altered uric acid levels and disease states. J Pharmacol Exp Ther. 2008;324:1–7.
• Sautin YY, Nakagawa T, Zharikov S, Johnson RJ. Adverse effects of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress. Am J Physiol Cell Physiol.
• Glantzounis G, Tsimoyiannis E, Kappas A, Galaris D. Uric acid and oxidative stress. Curr Pharm Des. 2005;11:4145–51.
• Grimsrud PA, Picklo MJ, Griffin TJ, Bernlohr DA. Carbonylation of adipose proteins in obesity and insulin resistance: Identification of adipocyte fatty acid-binding protein as a cellular target of 4- hydroxynonenal. Mol Cell Proteomics. 2007;6:624–37.
• Curtis JM, Grimsrud PA, Wright WS, Xu X, Foncea RE, Graham DW et al. Down regulation of adipose glutathione s-transferase A4 leads to increased protein carbonylation, oxidative stress, and mitochondrial dysfunction. Diabetes. 2010;59:1132–42.
• Yu R, Navab M. Oxidation hypothesis of atherogenesis: HDL inflammatory index and apolipoprotein A-I mimetic peptides. Future Cardiol. 2007;3:309–19.
• Manea A, Simionescu M. Nox enzymes and oxidative stress in atherosclerosis. Front Biosci. (Schol. Ed.) 2012;4:651–70.
• McMahon M, Grossman J, Fitz Gerald J, Dahlin-Lee, E.; Wallace DJ, Thong BY et al. Proinflammatory high-density lipoprotein as a biomarker for atherosclerosis in patients with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum. 2006;54:2541–49.
• Zarkovic M. The role of oxidative stress on the pathogenesis of graves’ disease. J. Thyroid Res. 2012;2012:302537.
• Melo A, Monteiro L, Lima R M, de Oliveira DM, de Cerqueira MD, El-Bacha RS. Oxidative stress in
• neurodegenerative diseases: mechanisms and therapeutic perspectives.
• Oxidative medicine and
• cellular longevity, 2011;2011.
• Butterfield A, Perluigi M, Reed T, Muharib T, Hughes CP, Robinson RA et al. Redox proteomics in selected neurodegenerative disorders: From its infancy to future applications. Antioxid Redox Signal. 2012;17:1610–55.
• Vaziri ND, Navab M, Fogelman AM. HDL metabolism and activity in chronic kidney disease. Nat Rev Nephrol. 2010;6:287–96.
• Johnson-Davis KL, Fernelius C, Eliason NB, Wilson A, Beddhu S, Roberts WL. Blood enzymes and oxidative stress in chronic kidney disease: A cross sectional study. Ann. Clin. Lab Sci. 2011;41:331–9.
• Arsova-Sarafinovska Z, Eken A, Matevska N, Erdem O, Sayal A, Savaser A et al. Increased oxidative/nitrosative stress and decreased antioxidant enzyme activities in prostate cancer. Clin Biochem. 2009;42:1228–35.
• Maffei F, Angeloni C, Malaguti M, Moraga JM, Pasqui F, Poli C et al. Plasma antioxidant enzymes and clastogenic factors as possible biomarkers of colorectal cancer risk. Mutat Res. 2011;714:88– 92.
• Kastle M, Grune T. Protein oxidative modification in the aging organism and the role of the ubiquitin proteasomal system. Curr Pharm Des. 2011;17:4007–22.
• Watanabe S, Kang DH, Feng L. Uric acid, hominoid evolution and the pathogenesis of salt- sensitivity. Hypertension. 2002;40:355–60.
• Parmar MS. Uric acid and cardiovascular risk. N Engl J Med. 2009;360:539.
• Spitsin SV, Scott GS, Mikheeva T. Comparison of uric acid and ascorbic acid in protection against EAE. Free Radic Biol Med. 2002;33:1363–71.
• Ames BN, Cathcart R, Schwiers E, Hochstein P. Uric acid provides an antioxidant defense in human against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci. 1981;78:6858–62.
• Davies KJ, Sevanian A, Muakkassah-Kelly SF, Hochstein P. Uric acid-iron ion complexes: a new aspect of the anti-oxidant functions of uric acid. Biochem J. 1986;235:747–54.
• Simie MG, Jovanovic SV. Antioxidation mechanisms of uric acid. Jam Chem Soc. 1989;111:5778– 82.
• Squadrito GL, Cueto R, Splenser AE, Valavanidis A, Zhang H, Uppu RM et al. Reaction of uric acid with peroxynitrite and implications for the mechanism of neuroprotection by uric acid. Arch Biochem Biophys. 2000;376:333–7
• Hink HU, Santanam N, Dikalov S, McCann L, Nguyen AD, Parthasarathy S, Harrison DG, Fukai T. Peroxidase properties of extracellular superoxide dismutase: role of uric acid in modulating in vivo activity. Arterioscler Thromb Vasc Biol. 2002;22:1402– 8.
• Maples KR, Mason RP. Free radical metabolite of uric acid. J Biol Chem. 1988;263:1709–12
• Nieto FJ, Iribarren C, Gross MD, Comstock GW, Cutler RG. Uric acid and serum antioxidant capacity: a reaction to atherosclerosis? Atherosclerosis. 2000;148:131–9.
• Baker JF, Krishnan E, Chen L, Schumacher HR. Serum uric acid and cardiovascular disease: recent developments, and where do they leave us? Am J Med. 2005;118:816–26.
• Reyes AJ. The increase in serum uric acid concentration caused by diuretics might be beneficial in heart failure. Eur J Heart Failure. 2005;7:461–7.
• Pasalic D, Marinkovic N, Turkovic LF. Uric acid as one of the important factors in multifactorial disorders – facts and Controversies. Biochemia Medica. 2012; 22:63–75.
• Makovey J, Macara M, Chen JS, Hayward CS, Seibel MJ, Sambrook PN et al. Serum uric acid plays a protective role for bone loss in peri and postmenopausal women: A longitudinal study. Bone. 2013;52:400–6.
• Bannon M. Is uric acid good for you? Q J Med. 2011;104:1013.
• Cong-cong S, Fei-fei L, Lei W, Mi L, Guo-fei L, Zhuo-lin L et al. Association of serum uric acid levels with the progression of Parkinson’s disease in Chinese patients. Chinese Medical Journal. 2012;125:583-7.
• de Oliveira EP, Burini RC. High plasma uric acid concentration: causes and consequences. Diabetol Metab Syndr. 2012;4:12.
• Johnson R J, Kang DH, Feig D. Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension. 2003;41:1183-90.
• Cigolini M, Targher G, Tonoli M, Manara F, Muggeo M, De Sandre G. Hyperuricaemia: relationships to body fat distribution and other components of the insulin resistance syndrome in 38-year-old healthy men and women. Int J Obes Relat Metab Disord. 1995;19:92–6.
• Chu NF, Wang DJ, Liou SH, Shieh SM. Relationship between hyperuricemia and other cardiovascular disease risk factors among adult males in Taiwan. Eur J Epidemiol. 2000;16:13–17.
• Yeh CJ, Pan WH, Jong YS, Kuo YY, Lo CH. Incidence and predictors of isolated systolic hypertension and isolated diastolic hypertension in Taiwan. J Formos Med Assoc. 2001;100:668–75.
• Leite ML. Uric acid and fibrinogen: age-modulated relationships with blood pressure components. J Hum Hypertens. 2010;25:1865-9.
• Kosugi T, Nakagawa T, Kamath D, Johnson RJ. Uric acid and hypertension: an age-related relationship? J Hum Hypertens. 2009;23:75–6.
• Lu Z, Dong B, Wu H, Chen T, Zhang Y, Wu J, Xiao H. Serum uric acid level in primary hypertension among Chinese nonagenarians/centenarians. J Hum Hypertens. 2009;23:113–21.
• Forman JP, Choi H, Curhan GC. Plasma uric acid level and risk for incident hypertension among men. J Am Soc Nephrol. 2007;18:287–92.
• Blacher J, Safar M. Specific aspects of high blood pressure in the elderly. J Renin Angiotensin Aldosterone Syst. 2002;3:S10–5.
• Barker DJ, Osmond C, Golding J, Kuh D, Wadsworth ME. Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. BMJ. 1989;298:564–7.
• Lee JE, Kim YG, Choi YH, Huh W, Kim DJ, Oh HY. Serum uric acid is associated with microalbuminuria in prehypertension. Hypertension. 2006;47:962–7.
• Tomita M, Mizuno S, Yamanaka H, Hosoda Y, Sakuma K, Matuoka Y et al. Does hyperuricemia affect mortality? A prospective cohort study of Japanese male workers. J Epidemiol. 2000;10:403–9.
• Iseki K, Oshiro S, Tozawa M, Iseki C, Ikemiya Y, Takishita S. Significance of hyperuricemia on the early detection of renal failure in a cohort of screened subjects. Hypertens Res. 2001;24:691–7.
• Iseki K, Ikemiya Y, Inoue T, Iseki C, Kinjo K, Takishita S. Significance of hyperuricemia as a risk factor for developing ESRD in a screened cohort. Am J Kidney Dis. 2004;44:642–50.
• Bellomo G, Venanzi S, Verdura C, Saronio P, Esposito A, Timio M. Association of uric acid with change in kidney function in healthy normotensive individuals. Am J Kidney Dis. 2010;56:264– 272.
• Alderman MH, Cohen H, Madhavan S, Kivlighn S. Serum uric acid and cardiovascular events in successfully treated hypertensive patients. Hypertension. 1999;34:144–50.
• Muscelli E, Natali A, Bianchi S, et al. Effect of insulin on renal sodium and uric acid handling in essential hypertension. Am J Hypertens. 1996;9:746–52.
• Strazzullo P, Barba G, Cappuccio FP, Siani A, Trevisan M, Farinaro E et al. Altered renal sodium handling in men with abdominal adiposity: a link to hypertension. J Hypertens. 2001;19:2157–64
• Culleton BF, Larson MG, Kannel WB, Levy D. Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study. Ann Intern Med. 1999;131:7–13.
• Franse LV, Pahor M, Di Bari M, Shorr RI, Wan JY, Somes GW et al. Serum uric acid, diuretic treatment and risk of cardiovascular events in the Systolic Hypertension in the Elderly Program (SHEP). J Hypertens. 2000;18:1149–54.
• Fang J, Alderman MH. Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study, 1971– 1992. National Health and Nutrition Examination Survey. JAMA. 2000;283:2404–10.
• Cappuccio FP, Strazzullo P, Farinaro E, Trevisan M. Uric acid metabolism and tubular Na handling. Results of a population based study. JAMA. 1993;270:354–9.
• Kirschbaum B. Renal regulation of plasma total antioxidant capacity. Med Hypotheses. 2001;56:625–9.
• McCoy SS, Crowson CS, Maradit-Kremers H, Therneau TM, Roger VL, Matteson EL et al. Longterm outcomes and treatment after myocardial infarction in patients with rheumatoid arthritis. J Rheumatol. 2013; 40:605-10.
• Lee KL, Woodlief LH, Topol EJ, Weaver WD, Betriu A, Col J et al. Predictors of 30-day mortality in the era of reperfusion for acute myocardial infarction. Circulation. 1995; 91:1659–68.
• Stone GW, Grines CL, Browne KF, Marco J, Rothbaum D, O'Keefe J et al. Predictors of in-hospital and 6-month outcome after acute myocardial infarction in the reperfusion era: the Primary Angioplasty in Myocardial Infarction (PAMI) trail. J Am Coll Cardiol. 1995;25:370–77.
• Carden DL, Granger DN. Pathophysiology of ischaemia-reperfusion injury. The Journal of pathology. 2000;190:255–66.
• Clark Wayne M. Reperfusion Injury in Stroke. eMedicine. WebMD. Retrieved 2006-08-09.
• Frohlich M, Imhof A, Berg G, Hutchinson WL, Pepys MB, Boeing H et al. Association between C- reactive protein and features of the metabolic syndrome: a population based study. Diabetes Care. 2000;23:1835–39.
• Leyva F, Anker SD, Godsland IF, Teixeira M, Hellewell PG, Kox WJ et al. Uric acid in chronic heart failure: a marker of chronic inflammation. Eur Heart J. 1998;19:1814–22.
• Olexa P, Olexova M, Gonsorcik J, Tkac I, Kisel’ova J, Olejnikova M. Uric acid a marker for systemic inflammatory response in patients with congestive heart failure? Wien Klin Wochenschr.
• Shi Y, Evans JE, Rock KL. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature. 2003;425:516–21.
• Kanellis J, Watanabe S, Li JH, Kang DH, Li P, Nakagawa T et al. Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2. Hypertension. 2003;416:1287–93.
• Johnson RJ, Rodriguez-Iturbe B, Kang DH, Feig DI, Herrera-Acosta J. A unifying pathway for essential hypertension. Am J Hypertens. 2005;18:431–40.
• Lv Q, Meng X-F, He F-F, Chen S, Su H, Xiong J et al. High serum uric acid and increased risk of type 2 diabetes: a systemic review and meta-analysis of prospective cohort studies. PLOS ONE. 2013;8:1-7.
• Koenig W, Meisinger C. Uric acid, type 2 diabetes, and cardiovascular diseases: fueling the common soil hypothesis? Clin Chem. 2008;54:231–3.
• Hayden MR, Tyagi SC. Uric acid: a new look at an old risk marker for cardiovascular disease, metabolic syndrome, and type 2 diabetes mellitus: the urate redox shuttle. Nutr Metab (Lond). 2004;1:10.
• Baker JF, Krishnan E, Chen L, Schumacher HR. Serum uric acid and cardiovascular disease: recent developments, and where do they leave us? Am J Med. 2005;118:816–26.
• Dehghan A, van Hoek M, Sijbrands EJ, Hofman A, Witteman JC. High serum uric acid as a novel risk factor for type 2 diabetes mellitus. Diabetes Care. 2008;31:361-2.
• Wang T, Bi Y, Xu M, Huang Y, Xu Y, et al. Serum uric acid associates with the incidence of type 2 diabetes in a prospective cohort of middle-aged and elderly Chinese. Endocrine. 2011;40:109–16.
• Viazzi F, Leoncini G, Vercelli M, Deferrari G, Pontremoli R. Serum uric acid levels predict new- onset type 2 diabetes in hospitalized patients with primary hypertension: the MAGIC study. Diabetes Care. 2011;34:126–8.
• Bhole V, Choi JW, Kim SW, de Vera M, Choi H. Serum uric acid levels and the risk of type 2 diabetes: a prospective study. Am J Med. 2010;123:957–61.
• Khosla UM, Zharikov S, Finch JL, Nakagawa T, Roncal C, Mu W et al. Hyperuricemia induces endothelial dysfunction. Kidney Int. 2005;67:1739–42.
• Butler R, Morris AD, Belch JJ, Hill A, Struthers AD. Allopurinol normalizes endothelial dysfunction in type 2 diabetics with mild hypertension. Hypertension. 2000;35:746–51.
• Hamaguchi M, Kojima T, Takeda N, Nakagawa T, Taniguchi H, Fujii K et al. The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med. 2005;143:722-8.
• Sung KC, Ryan MC, Kim BS, Cho YK, Kim BI, Reaven GM. Relationships between estimates of adiposity, insulin resistance, and nonalcoholic fatty liver disease in a large group of nondiabetic Korean adults. Diabetes Care. 2007;30:2113-18.
• Sung KC, Ryan MC, Wilson AM. The severity of nonalcoholic fatty liver disease is associated with increased cardiovascular risk in a large cohort of non-obese Asian subjects. Atherosclerosis. 2009;203:581-6.
• Lonardo A, Carani C, Carulli N, Loria P. Endocrine NAFLD' a hormonocentric perspective of nonalcoholic fatty liver disease pathogenesis. J Hepatol. 2006;44:1196-1207.
• Yoo TW, Sung KC, Shin HS, Kim BJ, Kim BS, Kang JH et al. Relationship between serum uric acid concentration and insulin resistance and metabolic syndrome. Circ J. 2005;69:928-33.
• Li Y, Xu C, Yu C, Xu L, Miao M. Association of serum uric acid level with non-alcoholic fatty liver disease: a cross-sectional study. J Hepatol. 2009;50:1029-34.
• Chitturi S, Abeygunasekera S, Farrell GC, Holmes-Walker J, Hui JM, Fung C et al. NASH and insulin resistance: insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology. 2002;35:373-9.
• Pagano G, Pacini G, Musso G, Gambino R, Mecca F, Depetris N et al. Nonalcoholic steatohepatitis, insulin resistance, and metabolic syndrome: further evidence for an etiologic association. Hepatology. 2002;35:367-72.
• Correspondence Address / Yazışma Adresi