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Pathophysiology of circulating xanthine oxidoreductase: New emerging roles for a multi-tasking enzyme
Open accessAbstract
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 binding of plasma XO to ECs can lead to vascular dysfunction (45, 71, 562, 612, 1010).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [71]
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“is not lost when competitive, such as allopurinol, or non-competitive XOR inhibitors, such as febuxostat, inactivate Moco site (reviewed in [6]).”
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“It has been shown that several changes observed in placental tissue during in vitro altered perfusion are similar to those reported in placentae from certain pregnancy pathologies, suggesting that H/R may be one of the underlying patho-physiological mechanisms of many obstetric conditions.”
ResultXanthine oxidoreductase and its inhibitors: relevance for gout
Day, R. O., Kamel, B., Kannangara, D. R. W., Williams, K. M., & Graham, G. G. (2016) · Clinical Science · doi:10.1042/cs20160010 · Cited by 41
Xie, Z., Luo, X., Zou, Z., Zhang, X., Huang, F., Li, R., Liao, S., & Liu, Y. (2017) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2017.01.053 · Cited by 41
Pleskačová, A., Brejcha, S., Pácal, L., Kaňková, K., & Tomandl, J. (2016) · Chromatographia · doi:10.1007/s10337-016-3208-8 · Cited by 40
Chen, G., Ye, T., Chen, H., Zhao, Z.-Y., Tang, W.-Q., Wang, L., & Xia, J.-L. (2017) · Oncogenesis · doi:10.1038/oncsis.2017.81 · Cited by 42
Oxidative Stress: Promoter of Allergic Sensitization to Protease Allergens?
van Rijt, L. S., Utsch, L., Lutter, R., & van Ree, R. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18061112 · Cited by 40
“All NOX family members are transmembrane proteins that transport electrons across biological membranes to reduce oxygen to superoxide.”
BackgroundInfluentialPro-Aging Effects of Xanthine Oxidoreductase Products
Battelli, M. G., Bortolotti, M., Bolognesi, A., & Polito, L. (2020) · Antioxidants · doi:10.3390/antiox9090839 · Cited by 38
“Furthermore, the killing ability of XOR products has been exploited for the production of immunoconjugates with the purpose of eliminating undesired cells [35].”
BackgroundSelf-citationAndrés, C. M. C., de la Lastra, J. M. P., Andrés, C., Plou, F. J., & Pérez‐Lebeña, E. (2023) · Journal of Biochemical and Molecular Toxicology · doi:10.1002/jbt.23455 · Cited by 44
Zhang, W. (2023) · Advances in clinical chemistry · doi:10.1016/bs.acc.2023.05.003 · Cited by 39
Xanthine Oxidase/Dehydrogenase Activity as a Source of Oxidative Stress in Prostate Cancer Tissue
Veljković, A., Hadži-Djokić, J., Sokolovic, D. T., Bašić, D., Veličković, L. J., Stojanović, M., Popović, D., & Kocic, G. M. (2020) · Diagnostics · doi:10.3390/diagnostics10090668 · Cited by 36
“Besides proteolytic and cysteine disulphide modifications, XDH/XO protein phosphorylation or even limited proteolysis were also reported previously [40].”
BackgroundThe Intestinal Redox System and Its Significance in Chemotherapy‐Induced Intestinal Mucositis
Yu, Q., Zhang, H., Guo, Y., Han, B., & Jiang, P. (2022) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2022/7255497 · Cited by 36
“In humans, XOR is primarily located in the liver and intestine [34], whereas other human organs display minute XOR activity (Figure 1) [35, 36].”
In silico design and synthesis of targeted rutin derivatives as xanthine oxidase inhibitors
Malik, N., Dhiman, P., & Khatkar, A. (2019) · BMC Chemistry · doi:10.1186/s13065-019-0585-8 · Cited by 35
Rendić, S., Crouch, R. D., & Guengerich, F. P. (2022) · Archives of Toxicology · doi:10.1007/s00204-022-03304-3 · Cited by 37
Mineral Micronutrients in Asthma
Zajac, D. (2021) · Nutrients · doi:10.3390/nu13114001 · Cited by 33
Nitrite-stimulated Gastric Formation of S-nitrosothiols As An Antihypertensive Therapeutic Strategy
Oliveira‐Paula, G. H., & Tanus-Santos, J. E. (2018) · Current Drug Targets · doi:10.2174/1389450119666180816120816 · Cited by 33
Greene, E., Cauble, R. N., Dhamad, A. E., Kidd, M. T., Kong, B. C., Howard, S. M., Castro, H. F., Campagna, S. R., Bedford, M. R., & Dridi, S. (2020) · Frontiers in Veterinary Science · doi:10.3389/fvets.2020.00458 · Cited by 33
“Because hypoxanthine is very low under physiological conditions, our data suggested that hypoxanthine was build up with the progression of WB myopathy with concomitant production of reactive oxygen species (75, 76).”
BackgroundTian, R., Peng, R., Yang, Z., Peng, Y., & Lu, N. (2020) · Nitric Oxide · doi:10.1016/j.niox.2020.01.007 · Cited by 32
Early diabetic kidney disease: Focus on the glycocalyx
Yu, H., Song, Y.-Y., & Li, X. (2023) · World Journal of Diabetes · doi:10.4239/wjd.v14.i5.460 · Cited by 36
Klisic, A. N., Kocic, G. M., Kavarić, N., Jovanović, M., Stanišić, V., & Ninić, A. (2017) · Clinical and Experimental Medicine · doi:10.1007/s10238-017-0483-0 · Cited by 32
“In addition, high level of uric acid stimulates vascular smooth muscle cells proliferation and migration [11], and induces them to produce MCP-1 [23], thus further aggravating endothelial dysfunction.”
BackgroundKawachi, Y., Fujishima, Y., Nishizawa, H., Nakamura, T., Akari, S., Murase, T., Saito, T., Miyazaki, Y., Nagao, H., Fukuda, S., et al. (2021) · JCI Insight · doi:10.1172/jci.insight.144762 · Cited by 30
Hypoxanthine: a new paradigm to interpret the origin of transfusion toxicity.
Casali, E., Berni, P., Spisni, A., Baricchi, R., & Pertinhez, T. A. (2016) · Europe PMC (PubMed Central) · doi:10.2450/2015.0177-15 · Cited by 30
The Role of Uric Acid in the Acute Myocardial Infarction: A Narrative Review
Demiray, A., Afşar, B., Covic, A. C., Kuwabara, M., Ferro, C. J., Lanaspa, M. A., Johnson, R. J., & Kanbay, M. (2021) · Angiology · doi:10.1177/00033197211012546 · Cited by 31
“It has also been shown that XO and NADPH oxidase are closely related to ROS producers and that they can mutually activate each other.(36) Uric acid is likely to play a role in the progression of the atherosclerotic plaque in coronary arteries, by acting as a prooxidant that promotes lipoprotein oxidation; atherosclero…”
BackgroundNakatani, A., Nakatani, S., Ishimura, E., Murase, T., Nakamura, T., Sakura, M., Tateishi, Y., Tsuda, A., Kurajoh, M., Mori, K., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-15419-0 · Cited by 29
Xanthine oxidase is hyper-active in Duchenne muscular dystrophy
Lindsay, A., McCourt, P. M., Karachunski, P. I., Lowe, D. A., & Ervasti, J. M. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.10.404 · Cited by 30
“Evidence has shown that inflammatory and hypoxic conditions like that measured in DMD [14,44] can stimulate marked increases in XO mRNA and activity [45], thus potentially explaining the elevation in mdx mouse XO mRNA.”
Tamura, T., Sano, M., Matsuoka, T., Yoshizawa, J., Yamamoto, R., Katsumata, Y., Endo, J., Homma, K., Kajimura, M., Suzuki, M., et al. (2019) · Shock · doi:10.1097/shk.0000000000001459 · Cited by 29
“Xanthine oxidoreductase (XOR) is one of the major sources of ROS production after I/R injury (26, 27).”
BackgroundOxidation pathways underlying the pro-oxidant effects of apigenin
Andueza, A., García-Garzón, A., de Galarreta, M. R., Ansorena, E., Iraburu, M. J., López-Zabalza, M. J., & Martínez-Irujo, J. J. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.06.003 · Cited by 28
“In mammals, XO mRNA has been detected in most tissues, and the highest transcript levels are found in liver and intestine [38,55].”
BackgroundOliveira‐Paula, G. H., Pinheiro, L. C., Guimarães, D. A., Conde-Tella, S. O., Blanco, A. L. F., de Angelis, C. D., Schechter, A. N., & Tanus-Santos, J. E. (2016) · Redox Biology · doi:10.1016/j.redox.2016.04.001 · Cited by 27
“to uric acid in the metabolic pathway of purine degradation [1, 2].”
BackgroundKurajoh, M., Fukumoto, S., Emoto, M., Murase, T., Nakamura, T., Ishihara, T., Go, H., Yamamoto, K., Nakatani, S., Tsuda, A., et al. (2019) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm-2019-0199 · Cited by 27
Increased plasma xanthine oxidoreductase activity deteriorates coronary artery spasm
Watanabe, K., Shishido, T., Otaki, Y., Watanabe, T., Sugai, T., Toshima, T., Takahashi, T., Yokoyama, M., Kinoshita, D., Murase, T., et al. (2018) · Heart and Vessels · doi:10.1007/s00380-018-1207-4 · Cited by 26
“XOR pathways are one of the major ROS-generating systems in the vascular vessels.”
BackgroundInfluentialFuruhashi, M., Koyama, M., Matsumoto, M., Murase, T., Nakamura, T., Higashiura, Y., Tanaka, M., Moniwa, N., Ohnishi, H., Saitoh, S., et al. (2019) · Endocrine Journal · doi:10.1507/endocrj.ej19-0053 · Cited by 26
Otaki, Y., Watanabe, T., Konta, T., Watanabe, M., Asahi, K., Yamagata, K., Fujimoto, S., Tsuruya, K., Narita, I., Kasahara, M., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-71301-6 · Cited by 26
Pang, X., Tang, C., Guo, R., & Chen, X. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.108020 · Cited by 27
Metadata
- Authors
- Battelli, M. G., Bolognesi, A., & Polito, L.
- Affiliations
- University of Bologna (IT)
- Corresponding author
- 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)
- 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
- 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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