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

Ning Liu,Hu Xu,Hongquan Wei,Jie Jiang,Wentong Chen,Wenjie Lu,Qianqian Sun,Youzhi Xu,Xiaojuan Yu,Carlo G Tocchetti

doi:10.1155/2021/1470380

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.

Highlights

Uric acid is a heterocyclic organic compound with the formula C5H4N4O3 (7, 9-dihydro-1H-purine-2,6,8(3H)-trione) and has a molecular mass of 168 Da
These results indicated that the interconnection between urate metabolism and reactive oxygen species (ROS) production in hypertension and diabetes mellitus raise the possibility that xanthine oxidase (XO) inhibitors may reduce oxidative stress independently of serum UA levels
xanthine oxidoreductase (XOR) is a critical target of drug action in the treatment of hyperuricemia

Summary

Introduction

Uric acid is a heterocyclic organic compound with the formula C5H4N4O3 (7, 9-dihydro-1H-purine-2,6,8(3H)-trione) and has a molecular mass of 168 Da. The water solubility of uric acid and its related metal salts is rather low and temperature dependent. Studies have shown that overproduction from hepatic metabolism or renal under excretion or extrarenal under excretion, or both can result in higher serum uric acid (SUA), termed hyperuricemia, which is the main predisposing factor for gout [5]. In most mammalian species such as rats and mice, uric acid generated from purine metabolism is further degraded into the more soluble compound allantoin by uricase, an enzyme that is mostly found in the liver. XOR catalyzes the oxidation of xanthine to uric acid, with the accompanying production of ROS [11, 12] (Figure 1). Xanthine oxidoreductases (XORs) are critical enzymes for uric acid production, which includes xanthine oxidase (XO) and xanthine dehydrogenase (XDH). This article reviews the updated information available on the role of XOR inhibition

Pathogenesis of Hyperuricemia Focused on Oxidative Stress

Xanthine Oxidase Inhibition Studies

Findings

Conclusions