Cited by 260Gout, Hyperuricemia, Uric AcidBiochemical and Molecular ResearchNitric Oxide and Endothelin Effects

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Pathophysiology of circulating xanthine oxidoreductase: New emerging roles for a multi-tasking enzyme

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Battelli, Maria Giulia, Bolognesi, Andrea, Polito, Letizia·2014·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

DOI 10.1016/j.bbadis.2014.05.022

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Abstract

The enzyme xanthine oxidoreductase (XOR) catalyses the last step of purine degradation in the highest uricotelic primates as a rate-limiting enzyme in nucleic acid catabolism. Although XOR has been studied for more than a century, this enzyme continues to arouse interest because its involvement in many pathological conditions is not completely known. XOR is highly evolutionarily conserved; moreover, its activity is very versatile and tuneable at multiple-levels and generates both oxidant and anti-oxidant products. This review covers the basic information on XOR biology that is essential to understand its enzymatic role in human pathophysiology and provides a comprehensive catalogue of the experimental and human pathologies associated with increased serum XOR levels. The production of radical species by XOR oxidase activity has been intensively studied and evaluated in recent decades in conjunction with the cytotoxic consequences and tissue injuries of various pathological conditions. More recently, a role has emerged for the activity of endothelium-bound enzymes in inducing the vascular response to oxidative stress, which includes the regulation of pro-inflammatory and pro-thrombotic activities of endothelial cells. The possible physiological functions of circulating XOR and the products of its enzyme activity are presented here together with their implications in cardiovascular and metabolic diseases.

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The inhibition activity on tyrosinase, xanthine oxidase, and lipase of Musa balbisiana parts grown in Vietnam
Hoang, T. N. N., Ho, L. B. N., Nguyen, K. N. N., Dao, D. T. A., & Le, T. H. A. (2024) · Food Science & Nutrition · doi:10.1002/fsn3.4364 · Cited by 10
“Besides, XO is also a biological source of oxygen-derived free radicals, which cause numerous pathological states such as inflammation, ischemia, hepatitis, carcinogenesis, reperfusion, and aging due to oxidative damage to living tissues (Battelli et al., 2014).”
Background
Xanthine oxidoreductase gene polymorphisms are associated with high risk of sepsis and organ failure
Gao, L., Rafaels, N. M., Dudenkov, T. M., Damarla, M., Damico, R. L., Maloney, J. P., Moss, M. M., Martin, G. S., Sevransky, J., Shanholtz, C. B., et al. (2023) · Respiratory Research · doi:10.1186/s12931-023-02481-8 · Cited by 9
“With its capacity to generate ROS, XOR has been implicated in the development of tissue oxidative damage in a wide variety of respiratory and cardiovascular disorders such as ARDS, ischemia reperfusion injury, atherosclerosis, heart failure, and arterial hypertension [14, 48].”
Background
Clinical Significance of Elevated Xanthine Dehydrogenase Levels and Hyperuricemia in Patients with Sepsis
Matsuoka, M., Yamaguchi, J., & Kinoshita, K. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241813857 · Cited by 10
“However, ROS produced from XOR inside cells triggers cell injury [36], and blood XOR can spread to all organs in the body through the blood, causing tissue injury in remote organs, including the lungs [37] or kidneys [38], and triggering ARDS, or multiple organ failure [39].”
Background
Altered activity of xenobiotic detoxifying enzymes at menopause – A cross-sectional study
Tsiokou, V., Kilindris, T. V., Begas, E., Kouvaras, E., Kouretas, D., & Asprodini, E. K. (2019) · Environmental Research · doi:10.1016/j.envres.2019.109074 · Cited by 9
A Newly Developed Method-Based Xanthine Oxidoreductase Activities in Various Human Liver Diseases
Sato, K., Naganuma, A., Nagashima, T., Arai, Y., Mikami, Y., Nakajima, Y., Kanayama, Y., Murakami, T., Uehara, S., Uehara, D., et al. (2023) · Biomedicines · doi:10.3390/biomedicines11051445 · Cited by 8
“Thus, XOR is considered a source of ROS generation and consequently contributes to the occurrence of oxidative stress-associated tissue damage [7–9].”
Background
Untargeted metabolomics of saliva in pregnant women with and without gestational diabetes mellitus and healthy non-pregnant women
Li, Y., Feng, Y., Yang, Z., Zhou, Z., Jiang, D., & Luo, J. (2023) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2023.1206462 · Cited by 8
“Xanthine oxidoreductase (XOR) has two redox isoforms, xanthine dehydrogenase (XDH) and xanthine oxidase (XO), which is mainly found in capillary endothelial cells, and these two forms are interconvertible (Battelli et al., 2014).”
Background
Reactive Oxygen Species - Advances and Developments
Ahmad, R. (2023) · Biochemistry · doi:10.5772/intechopen.107774 · Cited by 9
Myocardin reverses insulin resistance and ameliorates cardiomyopathy by increasing IRS-1 expression in a murine model of lipodystrophy caused by adipose deficiency of vacuolar H+-ATPase V0d1 subunit
Yuan, W., Lin, H., Sun, Y., Liu, L., Yan, M., Song, Y., Zhang, X., Lu, X., Xu, Y., He, Q., et al. (2024) · Theranostics · doi:10.7150/thno.93192 · Cited by 8
Alcohol abuse is associated with enhanced pulmonary and systemic xanthine oxidoreductase activity
Fini, M. A., Gaydos, J., McNally, A., Karoor, V., & Burnham, E. L. (2017) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00570.2016 · Cited by 8
“Pack-year smoking n/a 17 [10-21] n/a 15 [4-20] 0.”
Dietary effects of Sideritis scardica “mountain tea” on human in vivo activities of xenobiotic metabolizing enzymes in healthy subjects
Begas, E., Kilindris, T. V., Kouvaras, E., Tsioutsioumi, A., Kouretas, D., & Asprodini, E. K. (2018) · Food and Chemical Toxicology · doi:10.1016/j.fct.2018.09.056 · Cited by 8
Classical Xanthinuria in Nine Israeli Families and Two Isolated Cases from Germany: Molecular, Biochemical and Population Genetics Aspects
Peretz, H., Lagziel, A., Bittner, F., Kabha, M., Shtauber-Naamati, M., Zhuravel, V., Usher, S., Rump, S., Wollers, S., Bork, B., et al. (2021) · Biomedicines · doi:10.3390/biomedicines9070788 · Cited by 8
“Elevated levels of XDH/XO in the serum were found in pathological situations, such as rheumatic and autoimmune diseases, schizophrenia, type 2 diabetes, hypertension, dyslipidemia and cancer, and it was proposed that proinflammatory and prothrombotic activities of endothelial cells induced by high levels of circulatin…”
Background
Allopurinol, Febuxostat, and Nonuse of Xanthine Oxidoreductase Inhibitor Treatment in Patients Receiving Hemodialysis: A Longitudinal Analysis
Ishii, T., Seya, N., Taguri, M., Wakui, H., Yoshimura, A., & Tamura, K. (2024) · Kidney Medicine · doi:10.1016/j.xkme.2024.100896 · Cited by 7
“34 Based on these reports, xanthine oxidoreductase inhibition may improve prognoses by reducing oxidative stress rather than lowering uric acid levels.”
Mechanisms and Therapeutic Strategies for Myocardial Ischemia-Reperfusion Injury in Diabetic States
Xue, J., Zhuang, J., Wang, X., Meng, T., Wu, J. Q., Zhang, X., & Zhang, G. (2024) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.4c00272 · Cited by 10
Inhibition of xanthine oxidoreductase with febuxostat, but not allopurinol, prevents inflammasome assembly and IL-1β release
Monteiro, L. D. B., Archambault, A., Starchuck, L., Magaña, A. A., Oh, J. H., Dubland, J. A., Rakić, B., Patterson, A. E., Verchere, C. B., & Geltink, R. I. K. (2025) · Life Science Alliance · doi:10.26508/lsa.202403191 · Cited by 7
“Clinically approved XOR inhibitors include febuxostat (Fbx), a small molecule that is a speci ﬁ c, non-competitive XOR inhibitor (Becker et al, 2005; Battelli et al, 2014), and allopurinol (Allo), which is a purine analogue that competitively limits XOR activity.”
Deficiency of GntR Family Regulator MSMEG_5174 Promotes Mycobacterium smegmatis Resistance to Aminoglycosides via Manipulating Purine Metabolism
Deng, W., Zheng, Z., Chen, Y., Yang, M., Yan, J., Li, W., Zeng, J., Xie, J., Gong, S., & Zeng, H. (2022) · Frontiers in Microbiology · doi:10.3389/fmicb.2022.919538 · Cited by 7
Comprehensive analysis of the relationship between xanthine oxidoreductase activity and chronic kidney disease
Zhang, Y., Ding, X., Guo, L., Zhong, Y., Xie, J., Xu, Y., Li, H., & Zheng, D. (2023) · iScience · doi:10.1016/j.isci.2023.107332 · Cited by 7
BIOCHEMICAL ROLE OF XANTHINE OXIDOREDUCTASE AND ITS NATURAL INHIBITORS: AN OVERVIEW
Mandava, K., & Batchu, U. R. (2016) · International Journal of Pharmacy and Pharmaceutical Sciences · doi:10.22159//ijpps.v8i10.13927 · Cited by 7
In Vitro Inhibition of Xanthine Oxidase Purified from Arthritis Serum Patients by Nanocurcumin and Artemisinin Active Compounds
AL-dulaimy, W. Y. M., Hussein, A. A., Mahdi, M. A., & Kadhom, M. A. (2023) · Molecules · doi:10.3390/molecules28135124 · Cited by 6
Effect of Topiroxostat on Reducing Oxidative Stress in the Aorta of Streptozotocin-Induced Diabetic Rats
Noda, M., Kikuchi, C., Tarui, R., Nakamura, T., Murase, T., Hori, E., & Matsunaga, T. (2022) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.b22-00694 · Cited by 6
Long-term dietary nitrate supplementation slows the progression of established atherosclerosis in ApoE−/− mice fed a high fat diet
Liu, Y., Croft, K. D., Mori, T. A., Gaspari, T. A., Kemp‐Harper, B. K., & Ward, N. C. (2023) · European Journal of Nutrition · doi:10.1007/s00394-023-03127-7 · Cited by 5
“While XOR is highly activated in liver and intestine, human endothelial cells from the microvasculature of several tissues also have high levels of XOR activity [47].”
Background
The impact of dietary Laminaria digitata and alginate lyase supplementation on the weaned piglet liver: A comprehensive proteomics and metabolomics approach
Ribeiro, D. M., Leclercq, C. C., Charton, S. A. B., Costa, M. M., Carvalho, D. F. P., Sergeant, K., Cocco, E., Renaut, J., Freire, J. P. B., Prates, J. A. M., et al. (2023) · Journal of Proteomics · doi:10.1016/j.jprot.2023.105063 · Cited by 6
Potential Opportunities for Pharmacogenetic-Based Therapeutic Exploitation of Xanthine Dehydrogenase in Cardiovascular Disease
Massimo, G., Dyson, N., Olotu, F. A., Khambata, R. S., & Ahluwalia, A. (2024) · Antioxidants · doi:10.3390/antiox13121439 · Cited by 7
“The enzyme is ubiquitously expressed (mRNA identified in most tissues/cells); however, activity levels are low in most tissues with high expression levels being evident in few cell types/tissues (reviewed in [1]).”
The Effects of Topiroxostat, a Selective Xanthine Oxidoreductase Inhibitor, on Arterial Stiffness in Hyperuricemic Patients with Liver Dysfunction: A Sub-Analysis of the BEYOND-UA Study
Fujishima, Y., Nishizawa, H., Kawachi, Y., Nakamura, T., Akari, S., Ono, Y., Fukuda, S., Kita, S., Maeda, N., Hoshide, S., et al. (2023) · Biomedicines · doi:10.3390/biomedicines11030674 · Cited by 7
“Generation of XOR-dependent vascular ROS has been considered one of the underlying mechanisms responsible for endothelial dysfunction and atherosclerosis associated with hyperuricemia [9,10].”
Background
The Good and the Bad: The Bifunctional Enzyme Xanthine Oxidoreductase in the Production of Reactive Oxygen Species
Seychell, B. C., Vella, M., Hunter, G. J., & Hunter, T. (2023) · Biochemistry · doi:10.5772/intechopen.112498 · Cited by 7
Accumulation of Amino-Polyvinyl Alcohol-Coated Superparamagnetic Iron Oxide Nanoparticles in Bone Marrow: Implications for Local Stromal Cells
Schulze, F., Gramoun, A., Crowe, L. A., Dienelt, A., Akcan, T., Hofmann, H., Vallée, J., Duda, G. N., & Ode, A. (2015) · Nanomedicine · doi:10.2217/nnm.15.62 · Cited by 6
Involvement of xanthine oxidase activity with oxidative and inflammatory renal damage in silver catfish experimentally infected with Streptococcus agalactiae: Interplay with reactive oxygen species and nitric oxide
Souza, C. F., Baldissera, M. D., Moreira, K. L. S., da Rocha, M. I. D. U. M., da Veiga, M. L., Santos, R. C. V., & Baldisserotto, B. (2017) · Microbial Pathogenesis · doi:10.1016/j.micpath.2017.08.010 · Cited by 6
Role of AMP deaminase in diabetic cardiomyopathy
Miura, T., Kouzu, H., Tanno, M., Tatekoshi, Y., & Kuno, A. (2024) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-024-04951-z · Cited by 5
Proof of concept: hypoxanthine from stored red blood cells induces neutrophil activation.
Marraccini, C., Merolle, L., Casali, E., Baricchi, R., & Pertinhez, T. A. (2022) · Blood transfusion · doi:10.2450/2020.0208-20 · Cited by 5
Identification of a novel xanthine oxidoreductase inhibitor for hyperuricemia treatment with high efficacy and safety profile
Li, X., Chen, D., Qi, C., Yang, Y., Guo, K., Ma, C., Tian, J., Li, J., Zhang, L., Wang, B., et al. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.117223 · Cited by 5
Flavonoid-enriched fractions from Parastrephia lucida: Phytochemical, anti-inflammatory, antioxidant characterizations, and analysis of their toxicity
D’Almeida, R. E., Torres‐Carro, R., Simonetta, S. H., Zampini, I. C., Simirgiotis, M. J., Bórquez, J., Isla, M. I., & Alberto, M. R. (2020) · South African Journal of Botany · doi:10.1016/j.sajb.2020.09.019 · Cited by 5
Time-Dependent Changes in Plasma Xanthine Oxidoreductase During Hospitalization of Acute Heart Failure
Okazaki, H., Shirakabe, A., Matsushita, M., Shibata, Y., Shigihara, S., Sawatani, T., Tani, K., Kiuchi, K., Otsuka, Y., Murase, T., et al. (2020) · ESC Heart Failure · doi:10.1002/ehf2.13129 · Cited by 5
Pteridine and tryptophan pathways in children with type 1 diabetes: Isoxanthopterin as an indicator of endothelial dysfunction
Özer, Y., Cansever, M. Ş., Turan, H., Bayramoğlu, E., Aydın, D. B., İşat, E., Ceyhun, E., Zübarioğlu, T., Zeybek, A. Ç. A., Kıykım, E., et al. (2024) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2024.116072 · Cited by 4
An early accumulation of serum uric acid confers more risk of heart failure: a 10-year prospective cohort study
Tian, X., Chen, S., Zhang, Y., Xia, X., Xu, Q., Wu, S., & Wang, A. (2024) · European Heart Journal - Quality of Care and Clinical Outcomes · doi:10.1093/ehjqcco/qcae054 · Cited by 4
Xanthine Oxidase Perspective in Human Health
Dash, S., Pattanayak, S., Jena, B., Panda, M. K., & Singh, Y. D. (2020) · Current Biotechnology · doi:10.2174/2211550109999201113101040 · Cited by 4
Metabolomic analysis reveals the metabolic disturbance in aortic dissection: Subtype difference and accurate diagnosis
Zhang, J., Han, L., Liu, H., Zhang, H., & An, Z. (2023) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2023.05.006 · Cited by 4
Metabolomic signatures for blood pressure from early to late adolescence: findings from a U.S. cohort
Zhang, M., Perng, W., Rifas‐Shiman, S. L., Aris, I. M., Oken, E., & Hivert, M. (2024) · Metabolomics · doi:10.1007/s11306-024-02110-5 · Cited by 4
“The urate production process also generates reactive oxygen species that lead to oxidative stress, endothelial dysfunction, and impairments in cardiac and vascular functions (Battelli et al., 2014; Cai & Harrison, 2000).”
Characteristics of Patients with an Abnormally Decreased Plasma Xanthine Oxidoreductase Activity in Acute Heart Failure Who Visited the Emergency Department
Shirakabe, A., Okazaki, H., Matsushita, M., Shibata, Y., Goda, H., Shigihara, S., Asano, K., Tani, K., Kiuchi, K., Murase, T., et al. (2020) · Cardiology · doi:10.1159/000508037 · Cited by 4
Urinary Isoxanthopterin in Heart Failure Patients
Hori, M., Imamura, T., Kataoka, N., Nakamura, M., Tanaka, S., Onoda, H., Ushijima, R., Sobajima, M., Fukuda, N., Ueno, H., et al. (2021) · Circulation Reports · doi:10.1253/circrep.cr-21-0112 · Cited by 3
Uric Acid Levels and Cardiovascular and Cerebrovascular Diseases: A Mendelian Randomization Study
Hou, X., Cen, K., Zhu, Y., Zhu, Z. M., Zhang, Z., & Xu, F. (2024) · Cerebrovascular Diseases · doi:10.1159/000541624 · Cited by 3
Impact of Plasma Xanthine Oxidoreductase Activity on the Mechanisms of Distal Symmetric Polyneuropathy Development in Patients with Type 2 Diabetes
Fujishiro, M., Ishihara, H., Ogawa, K., Murase, T., Nakamura, T., Watanabe, K., Sakoda, H., Ono, H., Yamamotoya, T., Nakatsu, Y., et al. (2021) · Biomedicines · doi:10.3390/biomedicines9081052 · Cited by 3
“XOR-derived ROS involvement in the pathogenesis of tissue lesions induced by reperfusion after ischemia is thought to be related to vascular injury resulting from diabetic vascular complications [46].”
Background
Dexamethasone increases renal free fatty acids and xanthine oxidase activity in female rats: could there be any gestational impact?
Badmus, O. O., Sabinari, I. W., & Olatunji, L. A. (2020) · Drug and Chemical Toxicology · doi:10.1080/01480545.2020.1784190 · Cited by 3
“Xanthine oxidase is a metalloflavoprotein with a known role in the production of secondary messengers that mediate inflammation by generating superoxide anion and cell-damaging hydroxyl radicals (Battelli et al. 2014).”
Background
Promising Probiotic Food Supplement Based on Combination of Yeast Beta-Glucan, Bioselenium and Lactoferrin for Animal Health
de la Riva, G. A. D. L. R. (2020) · Biomedical Journal of Scientific & Technical Research · doi:10.26717/bjstr.2020.32.005271 · Cited by 3
“The found normal levels evidenced that physiological conditions didn’t affect animal health and have overall positive effect [54,55].”
Background

Authors: Battelli, M. G., Bolognesi, A., & Polito, L.
Affiliations: University of Bologna (IT)
Corresponding author: Bolognesi, Andrea
Polito, Letizia
ORCID: Battelli, Maria Giulia
Bolognesi, Andrea
Polito, Letizia
Venue: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
Publisher: Elsevier BV
Published: 2014-09
Volume: 1842
Issue: 9
Pages: 1502-1517
ISSN: 0925-4439 (ISSN-L)
DOI: 10.1016/j.bbadis.2014.05.022
OpenAlex: W2073007450
Cited by: 256
References: 308
Citations by year: 2026: 15 · 2025: 10 · 2024: 23 · 2023: 29 · 2022: 20 · 2021: 30 · 2020: 30 · 2019: 24 · 2018: 20 · 2017: 21 · 2016: 16 · 2015: 17 · 2014: 1
FWCI: 2.66
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by-nc-nd/3.0/ (vor)
Locations: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
INFM-OAR (INFN Catania) (submittedVersion, cc-by-nc-nd)
Funders: Alma Mater Studiorum‐University of Bologna
Pallotti Legacies for Cancer Research
Topics: Health Sciences › Medicine › Nephrology › Gout, Hyperuricemia, Uric Acid
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
Keywords: xanthine oxidoreductase, purine degradation, uric acid, oxidative stress, reactive oxygen species, endothelial cells, vascular response, inflammation, thrombosis, cardiovascular disease, metabolic disorders, serum enzyme levels
MeSH terms: Animals, Cardiovascular Diseases, Humans, Xanthine Dehydrogenase, Metabolic Syndrome

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Pathophysiology of circulating xanthine oxidoreductase: New emerging roles for a multi-tasking enzyme

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