Independent association of plasma xanthine oxidoreductase activity with serum uric acid level based on stable isotope-labeled xanthine and liquid chromatography/triple quadrupole mass spectrometry: MedCity21 health examination registry
-
Masafumi Kurajoh
,
Shinya Fukumoto
Abstract
Background
We developed a novel high-sensitive assay for plasma xanthine oxidoreductase (XOR) activity that is not affected by the original serum uric acid level. However, the association of plasma XOR activity with that level has not been fully examined.
Methods
This cross-sectional study included 191 subjects (91 males, 100 females) registered in the MedCity21 health examination registry. Plasma XOR activity was determined using our assay for plasma XOR activity with [13C2,15N2] xanthine and liquid chromatography/triple quadrupole mass spectrometry. Serum levels of uric acid and adiponectin, and visceral fat area (VFA) obtained by computed tomography were measured, and insulin resistance was determined based on the homeostasis model assessment (HOMA-IR) index.
Results
The median values for uric acid and plasma XOR activity were 333 μmol/L and 26.1 pmol/h/mL, respectively. Multivariable linear regression analysis showed a significant and positive association of serum uric acid level (coefficient: 26.503; 95% confidence interval: 2.06, 50.945; p = 0.035) with plasma XOR activity independent of VFA and HOMA-IR, and also age, gender, alcohol drinking habit, systolic blood pressure, estimated glomerular filtration rate (eGFR), glycated hemoglobin A1c, triglyceride, and adiponectin levels. The “gender*XOR activity” interaction was not significant (p = 0.91), providing no evidence that gender modifies the relationship between plasma XOR activity and serum uric acid level.
Conclusions
Plasma XOR activity was found to be positively associated with serum uric acid level independent of other known confounding factors affecting that level, including gender difference, eGFR, adiponectin level, VFA, and HOMA-IR.
Acknowledgments
We thank Maya Yoshida and Akane Utsunomiya for their assistance with the imaging procedures.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: This study was supported in part by research grants from Sanwa Kagaku Kenkyusho (to M.K.), Taisho Toyama Pharmaceutical Co. (to S.F.), Takeda Pharmaceuticals (to S.F.), Mitsubishi Tanabe Pharma Corporation (to S.F.), Chugai Pharmaceutical Co. (to S.F.), and Astellas Pharma (to S.F.) (funder Id: http://dx.doi.org/10.13039/501100004948), as well the Osaka City University (OCU) Strategic Research Grant 2014, 2015, 2016 for top priority research (to S.F.), a grant-in-aid for scientific research from the Gout Research Foundation (to M.K.), and a JSPS KAKENHI grant (number 18K11132) (to S.F.).
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Scott JT, Holloway VP, Glass HI, Arnot RN. Studies of uric acid pool size and turnover rate. Ann Rheum Dis 1969;28:366–73.10.1136/ard.28.4.366Search in Google Scholar
2. Wu XW, Muzny DM, Lee CC, Caskey CT. Two independent mutational events in the loss of urate oxidase during hominoid evolution. J Mol Evol 1992;34:78–84.10.1007/BF00163854Search in Google Scholar
3. Krenitsky TA, Tuttle JV, Cattau EL, Jr., Wang P. A comparison of the distribution and electron acceptor specificities of xanthine oxidase and aldehyde oxidase. Comp Biochem Physiol B 1974;49:687–703.10.1016/0305-0491(74)90256-9Search in Google Scholar
4. Saksela M, Lapatto R, Raivio KO. Xanthine oxidoreductase gene expression and enzyme activity in developing human tissues. Biol Neonate 1998;74:274–80.10.1159/000014034Search in Google Scholar PubMed
5. Hille R, Nishino T. Flavoprotein structure and mechanism. 4. Xanthine oxidase and xanthine dehydrogenase. FASEB J 1995;9:995–1003.10.1096/fasebj.9.11.7649415Search in Google Scholar
6. Marcolongo R, Marinello E, Pompucci G, Pagani R. The role of xanthine oxidase in hyperuricemic states. Arthritis Rheum 1974;17:430–8.10.1002/art.1780170414Search in Google Scholar PubMed
7. Carcassi A, Marcolongo R, Jr., Marinello E, Riario-Sforza G, Boggiano C. Liver xanthine oxidase in gouty patients. Arthritis Rheum 1969;12:17–20.10.1002/art.1780120104Search in Google Scholar PubMed
8. Battelli MG, Bolognesi A, Polito L. Pathophysiology of circulating xanthine oxidoreductase: new emerging roles for a multi-tasking enzyme. Biochim Biophys Acta 2014;1842: 1502–17.10.1016/j.bbadis.2014.05.022Search in Google Scholar PubMed
9. Murase T, Nampei M, Oka M, Miyachi A, Nakamura T. A highly sensitive assay of human plasma xanthine oxidoreductase activity using stable isotope-labeled xanthine and LC/TQMS. J Chromatogr B Anal Technol Biomed Life Sci 2016; 1039:51–8.10.1016/j.jchromb.2016.10.033Search in Google Scholar PubMed
10. Murase T, Oka M, Nampei M, Miyachi A, Nakamura T. A highly sensitive assay for xanthine oxidoreductase activity using a combination of [(13)C2,(15)N2]xanthine and liquid chromatography/triple quadrupole mass spectrometry. J Labelled Comp Radiopharm 2016;59:214–20.10.1002/jlcr.3390Search in Google Scholar PubMed
11. Nakatani A, Nakatani S, Ishimura E, Murase T, Nakamura T, Sakura M, et al. Xanthine oxidoreductase activity is associated with serum uric acid and glycemic control in hemodialysis patients. Sci Rep 2017;7:15416.10.1038/s41598-017-15419-0Search in Google Scholar
12. Beckman JS, Parks DA, Pearson JD, Marshall PA, Freeman BA. A sensitive fluorometric assay for measuring xanthine dehydrogenase and oxidase in tissues. Free Radic Biol Med 1989;6:607–15.10.1016/0891-5849(89)90068-3Search in Google Scholar
13. Emoto M, Nishizawa Y, Maekawa K, Hiura Y, Kanda H, Kawagishi T, et al. Homeostasis model assessment as a clinical index of insulin resistance in type 2 diabetic patients treated with sulfonylureas. Diabetes Care 1999;22:818–22.10.2337/diacare.22.5.818Search in Google Scholar PubMed
14. Yokoyama H, Emoto M, Fujiwara S, Motoyama K, Morioka T, Komatsu M, et al. Quantitative insulin sensitivity check index and the reciprocal index of homeostasis model assessment in normal range weight and moderately obese type 2 diabetic patients. Diabetes Care 2003;26:2426–32.10.2337/diacare.26.8.2426Search in Google Scholar PubMed
15. Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 2009;53:982–92.10.1053/j.ajkd.2008.12.034Search in Google Scholar PubMed
16. Committee of the Japan Diabetes Society on the Diagnostic Criteria of Diabetes M, Seino Y, Nanjo K, Tajima N, Kadowaki T, Kashiwagi A, et al. Report of the committee on the classification and diagnostic criteria of diabetes mellitus. J Diabetes Invest 2010;1:212–28.10.1007/s13340-010-0006-7Search in Google Scholar
17. Nishimura A, Sawai T. Determination of adiponectin in serum using a latex particle-enhanced turbidimetric immunoassay with an automated analyzer. Clin Chim Acta 2006;371:163–8.10.1016/j.cca.2006.03.008Search in Google Scholar
18. Mikkelsen WM, Dodge HJ, Valkenburg H. The distribution of serum uric acid values in a population unselected as to gout or hyperuricemia: Tecumseh, Michigan 1959–1960. Am J Med 1965;39:242–51.10.1016/0002-9343(65)90048-3Search in Google Scholar
19. Choi HK, Ford ES. Haemoglobin A1c, fasting glucose, serum C-peptide and insulin resistance in relation to serum uric acid levels – the Third National Health and Nutrition Examination Survey. Rheumatology (Oxford) 2008;47:713–7.10.1093/rheumatology/ken066Search in Google Scholar
20. Takahashi S, Yamamoto T, Tsutsumi Z, Moriwaki Y, Yamakita J, Higashino K. Close correlation between visceral fat accumulation and uric acid metabolism in healthy men. Metabolism 1997;46:1162–5.10.1016/S0026-0495(97)90210-9Search in Google Scholar
21. Tamba S, Nishizawa H, Funahashi T, Okauchi Y, Ogawa T, Noguchi M, et al. Relationship between the serum uric acid level, visceral fat accumulation and serum adiponectin concentration in Japanese men. Intern Med 2008;47:1175–80.10.2169/internalmedicine.47.0603Search in Google Scholar
22. Facchini F, Chen YD, Hollenbeck CB, Reaven GM. Relationship between resistance to insulin-mediated glucose uptake, urinary uric acid clearance, and plasma uric acid concentration. J Am Med Assoc 1991;266:3008–11.10.1001/jama.1991.03470210076036Search in Google Scholar
23. Waud WR, Rajagopalan KV. Purification and properties of the NAD+-dependent (type D) and O2-dependent (type O) forms of rat liver xanthine dehydrogenase. Arch Biochem Biophys 1976;172:354–64.10.1016/0003-9861(76)90087-4Search in Google Scholar
24. Sakuma S, Fujimoto Y, Iwai M, Fujimoto K, Yasuda M, Nishida H, et al. Induction of the conversion of xanthine dehydrogenase to oxidase in rabbit liver by Cu2+, Zn2+ and selenium ions. J Pharm Pharmacol 1994;46:487–90.10.1111/j.2042-7158.1994.tb03832.xSearch in Google Scholar PubMed
25. Washio KW, Kusunoki Y, Murase T, Nakamura T, Osugi K, Ohigashi M, et al. Xanthine oxidoreductase activity is correlated with insulin resistance and subclinical inflammation in young humans. Metabolism 2017;70:51–6.10.1016/j.metabol.2017.01.031Search in Google Scholar PubMed
26. Fujimura Y, Yamauchi Y, Murase T, Nakamura T, Fujita SI, Fujisaka T, et al. Relationship between plasma xanthine oxidoreductase activity and left ventricular ejection fraction and hypertrophy among cardiac patients. PLoS One 2017;12:e0182699.10.1371/journal.pone.0182699Search in Google Scholar PubMed PubMed Central
27. Furuhashi M, Matsumoto M, Tanaka M, Moniwa N, Murase T, Nakamura T, et al. Plasma xanthine oxidoreductase activity as a novel biomarker of metabolic disorders in a general population. Circ J 2018;82:1892–99.10.1253/circj.CJ-18-0082Search in Google Scholar
28. Sunagawa S, Shirakura T, Hokama N, Kozuka C, Yonamine M, Namba T, et al. Activity of xanthine oxidase in plasma correlates with indices of insulin resistance and liver dysfunction in patients with type 2 diabetes mellitus and metabolic syndrome: a pilot exploratory study. J Diabetes Invest 2019;10:94–103.10.1111/jdi.12870Search in Google Scholar
29. Lee J, Sparrow D, Vokonas PS, Landsberg L, Weiss ST. Uric acid and coronary heart disease risk: evidence for a role of uric acid in the obesity-insulin resistance syndrome. The Normative Aging Study. Am J Epidemiol 1995;142:288–94.10.1093/oxfordjournals.aje.a117634Search in Google Scholar
30. Fabregat I, Revilla E, Machado A. Short-term control of the pentose phosphate cycle by insulin could be modulated by the NADPH/NADP ratio in rat adipocytes and hepatocytes. Biochem Biophys Res Commun 1987;146:920–5.10.1016/0006-291X(87)90618-8Search in Google Scholar
31. Nagao H, Nishizawa H, Tanaka Y, Fukata T, Mizushima T, Furuno M, et al. Hypoxanthine secretion from human adipose tissue and its increase in hypoxia. Obesity (Silver Spring) 2018;26:1168–78.10.1002/oby.22202Search in Google Scholar
32. Choi HK, Atkinson K, Karlson EW, Willett W, Curhan G. Purine-rich foods, dairy and protein intake, and the risk of gout in men. N Engl J Med 2004;350:1093–103.10.1056/NEJMoa035700Search in Google Scholar
33. Yamamoto T, Moriwaki Y, Takahashi S, Yamakita J, Tsutsumi Z, Ohata H, et al. Effect of ethanol and fructose on plasma uridine and purine bases. Metabolism 1997;46:544–7.10.1016/S0026-0495(97)90192-XSearch in Google Scholar
34. Kakutani-Hatayama M, Kadoya M, Okazaki H, Kurajoh M, Shoji T, Koyama H, et al. Nonpharmacological management of gout and hyperuricemia: hints for better lifestyle. Am J Lifestyle Med 2017;11:321–9.10.1177/1559827615601973Search in Google Scholar PubMed PubMed Central
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Articles in the same Issue
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- Editorial
- Advancements in mass spectrometry as a tool for clinical analysis: Part I
- Drug adherence, testing and therapeutic monitoring
- Hyphenated mass spectrometry techniques for assessing medication adherence: advantages, challenges, clinical applications and future perspectives
- Method development for quantitative determination of seven statins including four active metabolites by means of high-resolution tandem mass spectrometry applicable for adherence testing and therapeutic drug monitoring
- Validation of a liquid chromatography tandem mass spectrometry (LC-MS/MS) method to detect cannabinoids in whole blood and breath
- THC and CBD concentrations in blood, oral fluid and urine following a single and repeated administration of “light cannabis”
- Identification of metabolites of peptide-derived drugs using an isotope-labeled reporter ion screening strategy
- Validation according to European and American regulatory agencies guidelines of an LC-MS/MS method for the quantification of free and total ropivacaine in human plasma
- Enhanced specificity due to method specific limits for relative ion intensities in a high-performance liquid chromatography – tandem mass spectrometry method for iohexol in human serum
- Small molecule biomarkers
- Applying mass spectrometry-based assays to explore gut microbial metabolism and associations with disease
- Trimethylamine-N-oxide (TMAO) determined by LC-MS/MS: distribution and correlates in the population-based PopGen cohort
- Development of a total serum testosterone, androstenedione, 17-hydroxyprogesterone, 11β-hydroxyandrostenedione and 11-ketotestosterone LC-MS/MS assay and its application to evaluate pre-analytical sample stability
- Short-term stability of free metanephrines in plasma and whole blood
- Validation of a rapid, comprehensive and clinically relevant amino acid profile by underivatised liquid chromatography tandem mass spectrometry
- UPLC-MS/MS method for determination of retinol and α-tocopherol in serum using a simple sample pretreatment and UniSpray as ionization technique to reduce matrix effects
- Independent association of plasma xanthine oxidoreductase activity with serum uric acid level based on stable isotope-labeled xanthine and liquid chromatography/triple quadrupole mass spectrometry: MedCity21 health examination registry
- Serum bile acids profiling by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and its application on pediatric liver and intestinal diseases
- LC-MS/MS analysis of plasma glucosylsphingosine as a biomarker for diagnosis and follow-up monitoring in Gaucher disease in the Spanish population
- Dried blood spots and alternative sample mediums
- Investigating the suitability of high-resolution mass spectrometry for newborn screening: identification of hemoglobinopathies and β-thalassemias in dried blood spots
- Candidate reference method for determination of vitamin D from dried blood spot samples
- Therapeutic drug monitoring of anti-epileptic drugs – a clinical verification of volumetric absorptive micro sampling
- Simultaneous quantitation of five triazole anti-fungal agents by paper spray-mass spectrometry
- Obtaining information from the brain in a non-invasive way: determination of iron in nasal exudate to differentiate hemorrhagic and ischemic strokes
Articles in the same Issue
- Frontmatter
- Editorial
- Advancements in mass spectrometry as a tool for clinical analysis: Part I
- Drug adherence, testing and therapeutic monitoring
- Hyphenated mass spectrometry techniques for assessing medication adherence: advantages, challenges, clinical applications and future perspectives
- Method development for quantitative determination of seven statins including four active metabolites by means of high-resolution tandem mass spectrometry applicable for adherence testing and therapeutic drug monitoring
- Validation of a liquid chromatography tandem mass spectrometry (LC-MS/MS) method to detect cannabinoids in whole blood and breath
- THC and CBD concentrations in blood, oral fluid and urine following a single and repeated administration of “light cannabis”
- Identification of metabolites of peptide-derived drugs using an isotope-labeled reporter ion screening strategy
- Validation according to European and American regulatory agencies guidelines of an LC-MS/MS method for the quantification of free and total ropivacaine in human plasma
- Enhanced specificity due to method specific limits for relative ion intensities in a high-performance liquid chromatography – tandem mass spectrometry method for iohexol in human serum
- Small molecule biomarkers
- Applying mass spectrometry-based assays to explore gut microbial metabolism and associations with disease
- Trimethylamine-N-oxide (TMAO) determined by LC-MS/MS: distribution and correlates in the population-based PopGen cohort
- Development of a total serum testosterone, androstenedione, 17-hydroxyprogesterone, 11β-hydroxyandrostenedione and 11-ketotestosterone LC-MS/MS assay and its application to evaluate pre-analytical sample stability
- Short-term stability of free metanephrines in plasma and whole blood
- Validation of a rapid, comprehensive and clinically relevant amino acid profile by underivatised liquid chromatography tandem mass spectrometry
- UPLC-MS/MS method for determination of retinol and α-tocopherol in serum using a simple sample pretreatment and UniSpray as ionization technique to reduce matrix effects
- Independent association of plasma xanthine oxidoreductase activity with serum uric acid level based on stable isotope-labeled xanthine and liquid chromatography/triple quadrupole mass spectrometry: MedCity21 health examination registry
- Serum bile acids profiling by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and its application on pediatric liver and intestinal diseases
- LC-MS/MS analysis of plasma glucosylsphingosine as a biomarker for diagnosis and follow-up monitoring in Gaucher disease in the Spanish population
- Dried blood spots and alternative sample mediums
- Investigating the suitability of high-resolution mass spectrometry for newborn screening: identification of hemoglobinopathies and β-thalassemias in dried blood spots
- Candidate reference method for determination of vitamin D from dried blood spot samples
- Therapeutic drug monitoring of anti-epileptic drugs – a clinical verification of volumetric absorptive micro sampling
- Simultaneous quantitation of five triazole anti-fungal agents by paper spray-mass spectrometry
- Obtaining information from the brain in a non-invasive way: determination of iron in nasal exudate to differentiate hemorrhagic and ischemic strokes
