Background: Increased production of reactive oxygen species is a condition that is associated with, and plays a role in the progression of, various disorders such as hypertension, atherosclerosis, and diabetes. Purpose: To assess in vivo oxidative stress levels and antioxidant potential and to analyze the relationship with serum uric acid (UA) levels. Methods and Results: Oxidative stress levels (derivatives of reactive oxygen metabolites, d-ROMs) and antioxidant potential (biological antioxidant potential, BAP) were measured in individuals who underwent a general health screening test, and data were analyzed from 8,025 individuals (2,953 women and 5,072 men) who were free from UA-lowering medication. Higher serum UA levels were associated with increased levels of d-ROMs in both genders, and this trend was more prominent in women. In addition, higher UA levels were also associated with higher BAP in both genders, although the dose dependence was not apparent in men. These associations remained statistically significant after adjusting for age, blood pressure, renal function, albuminuria, C-reactive protein, and insulin resistance index. Conclusions: In individuals who underwent general health screening, serum UA levels were positively associated with both d-ROMs and BAP levels. Whether lowering of UA by lifestyle modification or by medication alters d-ROM/BAP levels awaits further investigations.

Keywords:
Oxidative stress, Antioxidant potentials, Uric acid
1.
Madamanchi NR, Runge MS: Mitochondrial dysfunction in atherosclerosis. Circ Res 2007;100:460-473.
2.
Hussain SP, Hofseth LJ, Harris CC: Radical causes of cancer. Nat Rev Cancer 2003;3:276-285.
3.
Grisham MB: Reactive oxygen species in immune responses. Free Radic Biol Med 2004;36:1479-1480.
4.
Birben E, Sahiner UM, Sackesen C, Erzurum S, Kalayci O: Oxidative stress and antioxidant defense. World Allergy Organ J 2012;5:9-19.
5.
Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN: Bilirubin is an antioxidant of possible physiological importance. Science 1987;235:1043-1046.
6.
Ihara H, Hashizume N, Hasegawa T, Yoshida M: Antioxidant capacities of ascorbic acid, uric acid, α-tocopherol, and bilirubin can be measured in the presence of another antioxidant, serum albumin. J Clin Lab Anal 2004;18:45-49.
7.
Sedlak TW, Saleh M, Higginson DS, Paul BD, Juluri KR, Snyder SH: Bilirubin and glutathione have complementary antioxidant and cytoprotective roles. Proc Natl Acad Sci USA 2009;106:5171-5176.
8.
Ishizaka N, Ishizaka Y, Takahashi E, Yamakado M, Hashimoto H: High serum bilirubin level is inversely associated with the presence of carotid plaque. Stroke 2001;32:580-583.
9.
Novotny L, Vitek L: Inverse relationship between serum bilirubin and atherosclerosis in men: a meta-analysis of published studies. Exp Biol Med (Maywood) 2003;228:568-571.
10.
Ishizaka N, Ishizaka Y, Nagai R, Toda E, Hashimoto H, Yamakado M: Association between serum albumin, carotid atherosclerosis, and metabolic syndrome in Japanese individuals. Atherosclerosis 2007;193:373-379.
11.
Skak-Nielsen H, Torp-Pedersen C, Finer N, Caterson ID, Van Gaal L, James WP, Maggioni AP, Sharma AM, Coutinho W, Andersson C: Uric acid as a risk factor for cardiovascular disease and mortality in overweight/obese individuals. PLoS One 2013;8:e59121.
12.
Ishizaka N, Ishizaka Y, Toda E, Nagai R, Yamakado M: Association between serum uric acid, metabolic syndrome, and carotid atherosclerosis in Japanese individuals. Arterioscler Thromb Vasc Biol 2005;25:1038-1044.
13.
Saban-Ruiz J, Alonso-Pacho A, Fabregate-Fuente M, de la Puerta Gonzalez-Quevedo C: Xanthine oxidase inhibitor febuxostat as a novel agent postulated to act against vascular inflammation. Antiinflamm Antiallergy Agents Med Chem 2013;12:94-99.
14.
Ishizaka Y, Yamakado M, Toda A, Tani M, Ishizaka N: Relationship between estimated glomerular filtration rate, albuminuria, and oxidant status in the Japanese population. BMC Nephrol 2013;14:191.
15.
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC: Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412-419.
16.
Cesarone MR, Belcaro G, Carratelli M, Cornelli U, De Sanctis MT, Incandela L, Barsotti A, Terranova R, Nicolaides A: A simple test to monitor oxidative stress. Int Angiol 1999;18:127-130.
17.
Dohi K, Satoh K, Ohtaki H, Shioda S, Miyake Y, Shindo M, Aruga T: Elevated plasma levels of bilirubin in patients with neurotrauma reflect its pathophysiological role in free radical scavenging. In Vivo 2005;19:855-860.
18.
Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, Yamagata K, Tomino Y, Yokoyama H, Hishida A: Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 2009;53:982-992.
19.
Kamezaki F, Yamashita K, Kubara T, Suzuki Y, Tanaka S, Rkouzuma R, Okazaki M, Tasaki H, Otuji Y: Derivatives of reactive oxygen metabolites correlates with high-sensitivity C-reactive protein. J Atheroscler Thromb 2008;15:206-212.
20.
Hirose H, Kawabe H, Komiya N, Saito I: Relations between serum reactive oxygen metabolites and various inflammatory and metabolic parameters in a Japanese population. J Atheroscler Thromb 2009;16:77-82.
21.
Faienza MF, Francavilla R, Goffredo R, Ventura A, Marzano F, Panzarino G, Marinelli G, Cavallo L, Di Bitonto G: Oxidative stress in obesity and metabolic syndrome in children and adolescents. Horm Res Paediatr 2012;78:158-164.
22.
Piconi L, Quagliaro L, Ceriello A: Oxidative stress in diabetes. Clin Chem Lab Med 2003;41:1144-1149.
23.
Ceriello A, Lush CW, Darsow T, Piconi L, Corgnali M, Nanayakkara N, Frias JP, Maggs D: Pramlintide reduced markers of oxidative stress in the postprandial period in patients with type 2 diabetes. Diabetes Metab Res Rev 2008;24:103-108.
24.
Dohi K, Miyamoto K, Fukuda K, Nakamura S, Hayashi M, Ohtaki H, Shioda S, Aruga T: Status of systemic oxidative stress during therapeutic hypothermia in patients with post-cardiac arrest syndrome. Oxid Med Cell Longev 2013;2013:562429.
25.
Belcaro G, Hu S, Cesarone MR, Dugall M: A controlled study shows daily intake of 50 mg of French pine bark extract (Pycnogenol®) lowers plasma reactive oxygen metabolites in healthy smokers. Minerva Med 2013;104:439-446.
26.
Vassalle C, Vigna L, Bianchi S, Maffei S, Novembrino C, De Giuseppe R, de Liso F, Vannucci A, Tirelli S, Maiavacca R, Bamonti F: A biomarker of oxidative stress as a nontraditional risk factor in obese subjects. Biomark Med 2013;7:633-639.
27.
Fukui T, Yamauchi K, Maruyama M, Yasuda T, Kohno M, Abe Y: Significance of measuring oxidative stress in lifestyle-related diseases from the viewpoint of correlation between d-ROMs and BAP in Japanese subjects. Hypertens Res 2011;34:1041-1045.
28.
Sautin YY, Johnson RJ: Uric acid: the oxidant-antioxidant paradox. Nucleosides Nucleotides Nucleic Acids 2008;27:608-619.
29.
Ahn SH, Lee SH, Kim BJ, Lim KH, Bae SJ, Kim EH, Kim HK, Choe JW, Koh JM, Kim GS: Higher serum uric acid is associated with higher bone mass, lower bone turnover, and lower prevalence of vertebral fracture in healthy postmenopausal women. Osteoporos Int 2013;24:2961-2970.
30.
Ljubisavljevic S, Stojanovic I, Vojinovic S, Milojkovic M, Dunjic O, Stojanov D, Pavlovic D: Association of serum bilirubin and uric acid levels changes during neuroinflammation in patients with initial and relapsed demyelization attacks. Metab Brain Dis 2013;28:629-638.
31.
George J, Carr E, Davies J, Belch JJ, Struthers A: High-dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid. Circulation 2006;114:2508-2516.
32.
Fabbrini E, Serafini M, Baric IC, Hazen SL, Klein S: Effect of plasma uric acid on antioxidant capacity, oxidative stress, and insulin sensitivity in obese subjects. Diabetes 2014;63:976-981.
33.
Stojanov M, Stefanovic A, Dzingalasevic G, Ivanisevic J, Miljkovic M, Mandic-Radic S, Prostran M: Total bilirubin in young men and women: association with risk markers for cardiovascular diseases. Clin Biochem 2013;46:1516-1519.
34.
Kuwahata S, Hamasaki S, Ishida S, Kataoka T, Yoshikawa A, Orihara K, Ogawa M, Oketani N, Saihara K, Okui H, Shinsato T, Kubozono T, Ichiki H, Fujita S, Takumi T, Yoshino S, Nakazaki M, Miyata M, Tei C: Effect of uric acid on coronary microvascular endothelial function in women: association with eGFR and ADMA. J Atheroscler Thromb 2010;17:259-269.
35.
Kaneko K, Kimata T, Tsuji S, Shimo T, Takahashi M, Tanaka S: Serum albumin level accurately reflects antioxidant potentials in idiopathic nephrotic syndrome. Clin Exp Nephrol 2012;16:411-414.
36.
Dinour D, Gray NK, Campbell S, Shu X, Sawyer L, Richardson W, Rechavi G, Amariglio N, Ganon L, Sela BA, Bahat H, Goldman M, Weissgarten J, Millar MR, Wright AF, Holtzman EJ: Homozygous SLC2A9 mutations cause severe renal hypouricemia. J Am Soc Nephrol 2010;21:64-72.
37.
Kikuchi Y, Koga H, Yasutomo Y, Kawabata Y, Shimizu E, Naruse M, Kiyama S, Nonoguchi H, Tomita K, Sasatomi Y, Takebayashi S: Patients with renal hypouricemia with exercise-induced acute renal failure and chronic renal dysfunction. Clin Nephrol 2000;53:467-472.
38.
Kaneko K, Taniguchi N, Tanabe Y, Nakano T, Hasui M, Nozu K: Oxidative imbalance in idiopathic renal hypouricemia. Pediatr Nephrol 2009;24:869-871.
© 2014 S. Karger AG, Basel
2014
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.