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Review
. 2021 Mar 26:2021:1470380.
doi: 10.1155/2021/1470380. eCollection 2021.

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 , Wenjie Lu  1
Affiliations
Review

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

Ning Liu et al. Oxid Med Cell Longev. .

Abstract

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.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Purine metabolism. Adenosine monophosphate (AMP) is converted to inosine by forming inosine monophosphate (IMP) as an intermediate by AMP deaminase, or by nucleotidase to form adenosine followed by purine nucleoside phosphorylase (PNP) to form adenine; simultaneously, guanine monophosphate (GMP) is converted to guanosine by nucleotidase followed by PNP to form guanine. Moreover, AMP and GMP also have feedback regulation on 5-phosphoribosyl-1-pyrophosphate (PRPP). Hypoxanthine is oxidized to form xanthine by XOR which includes XDH and XO, and the conversion of guanine to xanthine occurs through the action of guanine deaminase. The enzyme hypoxanthine-guanine phosphoribosyl transferase (HGPRT) salvages hypoxanthine to IMP and GMP. In a similar salvage pathway, adenine phosphoribosyl transferase (APRT) converts adenine to AMP. Finally, XOR catalyzes the oxidation of xanthine to uric acid, with the accompanying production of ROS. In most mammalian species such as rats and mice, uric acid generated from purine metabolism is further degraded into allantoin by uricase, an enzyme that is mostly found in the liver. However, in humans and the great apes, uric acid is the endpoint of purine metabolism because the uricase gene is crippled. It is estimated that approximately 30% of uric acid excretion is by the intestine and renal mechanisms of urate excretion account for the other 70%.
Figure 2
Figure 2
Hyperuricemia and related diseases. Hyperuricemia occurs as a result of increased uric acid production, impaired renal uric acid excretion, or a combination of both mechanisms. In humans, normal SUA levels are 2.6–5.7 mg/dL (155–339 μmol/L) for women and 3.5–7.0 mg/dL (208–416 μmol/L) for men. Moreover, hyperuricemia may cause oxidative stress, inflammation, and endothelial dysfunction, and hyperuricemia is even more of a burden due to its association with multiple comorbidities, including gout, hypertension, cardiovascular disease, chronic kidney disease (CKD), stroke, atherosclerosis, and metabolic syndrome (MS).
Figure 3
Figure 3
Uric acid and oxidative stress. XOR, which is a critical enzyme in the production of uric acid, can produce O2– and H2O2. Then, the reaction between O2– and NO reduces NO bioavailability, which is a main cause of endothelial dysfunction. Moreover, O2– can undergo the disproportionation reaction into H2O2 by superoxide dismutase (SOD), and O2– and H2O2 can also be converted to the more cytotoxic oxidants peroxynitrate (ONOO–), hydroxyl anion (OH–), and hypochlorous acid (HOCl), which are more harmful to cells. These high levels of ROS result in oxidative stress. On the other hand, several experimental and clinical studies support a role for uric acid as a contributory causal factor in multiple conditions, including oxidation and antioxidant effects. The critical point is that UA becomes a strong prooxidant in the intracellular environment and is associated with various factors, such as inflammation and endothelial dysfunction.
Figure 4
Figure 4
Chemical structure of xanthine oxidoreductase (XOR) and XOR inhibitors. Xanthine oxidase (XOR) is the enzyme that catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid. XOR contains two forms: xanthine dehydrogenase (XDH) and xanthine oxidase (XO). XDH prefers NAD+ as the substrate, and XO prefers O2. XOR has 2 flavin molecules (FAD), 2 molybdenum atoms, and 8 iron atoms bound per enzymatic unit. The molybdenum atoms are the active sites of the enzyme, and the iron atoms are part of the [2Fe-2S] ferredoxin iron-sulfur clusters and participate in electron transfer reactions. XOR is a critical target of drug action in the treatment of hyperuricemia. XOR inhibitors are potentially effective drugs to control the related diseases and dysfunctions and include allopurinol, oxypurinol, febuxostat, and topiroxostat.
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