The Role of Oxidative Stress in Hyperuricemia and Xanthine Oxidoreductase (XOR) Inhibitors

Hindawi Oxidative Medicine and Cellular Longevity Volume 2021, Article ID 1470380, 15 pages https://doi.org/10.1155/2021/1470380 Review Article The Role of Oxidative Stress in Hyperuricemia and Xanthine Oxidoreductase (XOR) Inhibitors Ning Liu ,1 Hu Xu,1 Qianqian Sun,1 Xiaojuan Yu,1 Wentong Chen,1 Hongquan Wei,1 Jie Jiang,1,2 Youzhi Xu ,1 and Wenjie Lu 1 1Basic Medical College, Anhui Medical University, Hefei 230032, China 2College of Pharmacy, Anhui Medical University, Hefei 230032, China Correspondence should be addressed to Youzhi Xu; [email protected] and Wenjie Lu; [email protected] Received 19 May 2020; Revised 5 March 2021; Accepted 12 March 2021; Published 27 March 2021 Academic Editor: Carlo G. Tocchetti Copyright © 2021 Ning Liu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Uric acid is the end product of purine metabolism in humans. Hyperuricemia is a metabolic disease caused by the increased formation or reduced excretion of serum uric acid (SUA). Alterations in SUA homeostasis have been linked to a number of diseases, and hyperuricemia is the major etiologic factor of gout and has been correlated with metabolic syndrome, cardiovascular disease, diabetes, hypertension, and renal disease. Oxidative stress is usually defined as an imbalance between free radicals and antioxidants in our body and is considered to be one of the main causes of cell damage and the development of disease. Studies have demonstrated that hyperuricemia is closely related to the generation of reactive oxygen species (ROS). In the human body, xanthine oxidoreductase (XOR) catalyzes the oxidative hydroxylation of hypoxanthine to xanthine to uric acid, with the accompanying production of ROS. Therefore, XOR is considered a drug target for the treatment of hyperuricemia and gout. In this review, we discuss the mechanisms of uric acid transport and the development of hyperuricemia, emphasizing the role of oxidative stress in the occurrence and development of hyperuricemia. We also summarize recent advances and new discoveries in XOR inhibitors. 1. Introduction secretion and reabsorption in the kidney tubule, and excretion in the intestine. It is estimated that approximately 30% Uric acid is a heterocyclic organic compound with the for- of uric acid is excreted by the intestine and renal mechanisms mula C5H4N4O3 (7, 9-dihydro-1H-purine-2,6,8(3H)-trione) of urate excretion account for the other 70% [3]. In the and has a molecular mass of 168 Da. Uric acid was first iso- human kidney, three urate transporters, URAT1/SLC22A12, lated from kidney stones in 1776 by the Swedish chemist Carl GLUT9/SLC2A9, and ABCG2/BCRP, play vital roles in the Wilhelm Scheele [1]. Then, the Ukrainian chemist Ivan Hor- regulation of SUA, and the completion of urate reabsorption baczewski first synthesized uric acid by melting urea with gly- and secretion may occur through a complex array of mecha- cine in 1882 [2]. Uric acid is a diprotic acid with pKa1 = 5:4 nisms taking place in the proximal tubule [3, 4]. Studies have and pKa2 = 10:3; thus, it predominately exists as monoso- shown that overproduction from hepatic metabolism or dium urate (MSU) ion at physiological pH. In general, the renal under excretion or extrarenal under excretion, or both water solubility of uric acid and its related metal salts is rather can result in higher serum uric acid (SUA), termed hyperuri- low and temperature dependent. All these salts exhibit cemia, which is the main predisposing factor for gout [5]. greater solubility in hot water than cold water. In humans However, in most mammalian species such as rats and mice, and the great apes, uric acid is the endpoint of purine uric acid generated from purine metabolism is further metabolism. Alteration of SUA homeostasis depends on degraded into the more soluble compound allantoin by uri- the balance between production, the intricate processes of case, an enzyme that is mostly found in the liver. In humans, 2 Oxidative Medicine and Cellular Longevity the uricase gene is crippled by two mutations so that the in hyperuricemia-related diseases. Simultaneously, this arti- level of SUA in humans is much higher than other mam- cle reviews the updated information available on the role of mals [6, 7]. XOR inhibition. One of the most plentiful metabolite classes within a mammalian cell is purines. Purine is a heterocyclic aromatic 2. Pathogenesis of Hyperuricemia Focused on organic compound that consists of a pyrimidine ring fused to Oxidative Stress an imidazole ring and is water soluble. Purines are the most widely occurring nitrogen-containing heterocycles in nature 2.1. Asymptomatic Hyperuricemia. Hyperuricemia (HUA) in and are found in high concentrations in meat and meat prod- adults is defined as a serum uric acid level>420 μmol/L ucts, especially seafood and internal organs. Examples of (7 mg/dL) in men and >357 μmol/L (6 mg/dL) in women purine-rich foods include meats, organ meat (such as the [19, 20]. On the one hand, a diet rich in purine and/or fructose liver and kidney), seafood, legumes, yeast, mushrooms, can lead to an increase in serum uric acid. Briefly, fructose sweetbreads, sardines, brains, mackerel, scallops, and gravy is phosphorylated into fructose 1-phosphate in a reaction [8, 9]. Higher levels of meat or seafood consumption are catalyzed by fructokinase primarily during fructose metab- associated with an increased risk of gout, whereas proper olism and this reaction decreases the levels of intracellular intake of purine-rich vegetables or protein is not associated phosphate and ATP [13]. Next, the enzyme fructose-1-p with an increased risk of gout [10]. The metabolism of aldolase breaks fructose 1-phosphate into dihydroxyacetone purines is a complex system containing various enzymes. phosphate (DHAP) and D-glyceraldehyde. When there is a Adenosine monophosphate (AMP) is converted to inosine high intake of fructose, phosphorylation into fructose 1- by forming inosine monophosphate (IMP) as an intermedi- phosphate is fast, but the reaction with aldolase is slow. Thus, ate by AMP deaminase, or by nucleotidase to form adenosine fructose 1-phosphate accumulates, and decreased intracellu- followed by purine nucleoside phosphorylase (PNP) to form lar phosphate level stimulates AMP deaminase (AMPD), adenine; simultaneously, guanine monophosphate (GMP) is which catalyze the degradation of AMP to inosine monopho- converted to guanosine by nucleotidase followed by PNP to sphate [21]. And then, the purine degradation produces UA form guanine [4, 7]. Hypoxanthine is then oxidized to form [22]. Physiologically, fructose also stimulates UA synthesis xanthine by XOR (including XDH and XO), and the conver- from amino acid precursors such as glycine [23]. Moreover, sion of guanine to xanthine occurs through the action of gua- long-term fructose stimulation reduces renal excretion of nine deaminase. Finally, XOR catalyzes the oxidation of UA, resulting in elevated serum UA levels [24]. The intake xanthine to uric acid, with the accompanying production of of alcohol and excessive exercise can also cause an increase ROS [11, 12] (Figure 1). in the level of serum uric acid. Some malignant tumors also Hyperuricemia has become increasingly common over increase the level of serum uric acid after chemotherapeutic the last few decades, and the burden of hyperuricemia is drugs are used. On the other hand, more than 90% of hyper- made heavier by its association with multiple comorbidities, uricemia is caused by decreased uric acid excretion [25, 26]. including metabolic syndrome, cardiovascular disease, diabe- It is characterized by high uric acid levels in the blood, caus- tes, hypertension, and renal disease [13–15]. The association ing deposition of urate crystals in the joints and kidneys. In of hyperuricemia with related diseases has been described normal humans, uric acid is excreted in urine. However, uric since the late 19th century. Although the importance of these acid excretion may be impaired by kidney disease, leading to associations remains controversial, increasing data from pro- hyperuricemia. spective studies suggest that hyperuricemia is a key risk factor Asymptomatic hyperuricemia is a condition in which the for developing cardiovascular disease or other diseases. How- serum urate concentration is elevated (>7 mg/dL in men or ever, we still need more evidence to prove whether lowering >6 mg/dL in women) but there are no symptoms or signs of uric acid levels would be of clinical benefit in the prevention urate crystal deposition [27]. The increasing prevalence of or treatment of these diseases (Figure 2). asymptomatic hyperuricemia may be ascribable to the Oxidative stress can be defined as the condition in which expanding obesity epidemic, dietary changes, an aging popu- excessive production of reactive oxygen species (ROS) lation, and the increasing use of diuretics. In some patients occurs. In many disease states, oxidant-producing enzymes, with asymptomatic hyperuricemia, steady hyperuricemia is the major sources of ROS, are upregulated [16]. Recent stud- suggested to be sufficient to trigger MSU crystal deposition ies have demonstrated that asymptomatic young patients and MSU crystals can trigger inflammatory pathways (IL-6 with primary hyperuricemia had significantly higher oxida- and IL-8) [28, 29]. Numerous epidemiological data have tive stress than healthy

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