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

Liu, Ning; Hu, Xu; Sun, Qianqian; Yu, Xiao; Chen, Wen‐Tong; Wei, Hongquan; Jiang, Jie; Xu, Youzhi; Lu, Wenjie

doi:10.1155/2021/1470380

Cited by 98 publications

(97 citation statements)

References 159 publications

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“…As regards the production of ROS by XO, under conditions of oxidative stress, XO activity prevails to XDH activity, resulting in further ROS production. In cultures of endothelial cells, NOX maintains XO levels and XO is responsible for increased ROS production [36]. In this study, DMLE-70 had the strongest DPPH free radical scavenging activity and XOD-inhibitory activity among the DMLEs (Tables 2-4).…”

Section: Discussionmentioning

confidence: 54%

Antihyperuricemic Effect of Dendropanax morbifera Leaf Extract in Rodent Models

Lee

Kim

Han

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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Dendropanax morbifera is a well-known traditional medicine used in China and Korea to treat intestinal disorders, urosis, diuresis, and chronic glomerulonephritis. Hyperuricemia is a metabolic disorder characterized by a high uric acid level in serum due to an imbalance between uric acid production and excretion and causes gout. Recently, the prevalence of hyperuricemia worldwide has been continuously increasing. Xanthine oxidase (XOD) inhibitors (allopurinol (ALP) and febuxostat) and uricosuric agents (benzbromarone and probenecid) are used to treat hyperuricemia clinically. However, because these drugs are poorly tolerated and cause side effects, such as kidney diseases, hepatotoxicity, gastrointestinal symptoms, and hypersensitivity syndrome, only a limited number of drugs are available. We investigated the antihyperuricemic effects of Dendropanax morbifera leaf ethanol extract (DMLE) and its underlying mechanisms of action through in vitro and in vivo studies. We evaluated uric acid levels in serum and urine, and xanthine oxidase (XOD) inhibition activity in the serum and liver tissue of a hyperuricemic rat model of potassium oxonate (PO)-induced hyperuricemic rats. In vitro study, XOD-inhibitory activity was the lowest among the test substances at the IC50 of ALP. However, the IC50 of DMLE-70 was significantly low compared with that of other DMLEs ( p < 0.05 ). In PO-induced hyperuricemic rats, uric acid (UA) levels in serum and urine were significantly reduced in all DMLE-70 and allopurinol-treated (ALT) groups than in the PC group ( p < 0.05 ). UA levels in urine were lower than those in serum in all DME groups. In PO-induced hyperuricemic rats, DMEE-200 reduced UA concentration in serum and increased UA excretion in the urine. These findings suggest that DMLE exerts antihyperuricemic and uricosuric effects on promoting UA excretion by enhanced secretion and inhibition of UA reabsorption in the kidneys. Thus, DMLE may be a potential treatment for hyperuricemia and gout.

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Section: Discussionmentioning

confidence: 54%

Antihyperuricemic Effect of Dendropanax morbifera Leaf Extract in Rodent Models

Lee

Kim

Han

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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“…Xanthine oxidase, converted from xanthine dehydrogenase, acts as a key enzyme for the oxidation of hypoxanthine and xanthine during the production of uric acid in the liver. It is well known that the mitochondrial ROS are produced during the xanthine oxidase mediated production of uric acid [ 7 , 8 ]. We found an increase in the xanthine oxidase activity and xanthine dehydrogenase mRNA expression in hypoxanthine-treated HepG2 cells and the liver of potassium oxonate induced hyperuricemic mice as compared to that in the normal cells and liver of healthy mice.…”

Section: Discussionmentioning

confidence: 99%

“…Xanthine dehydrogenase is initially synthesized and can be converted to xanthine oxidase by reversible sulfhydryl oxidation or irreversible proteolysis [ 7 ]. During the production of uric acid, xanthine oxidase delivers electrons directly to molecular oxygen, thus generating the reactive oxygen species (ROS), including the superoxide anion (O 2 •− ) and hydrogen peroxide (H 2 O 2 ), which can further induce oxidative stress [ 8 ]. Approximately 75% of uric acid excretion occurs in the kidneys and approximately 25% occurs in the intestines.…”

Section: Introductionmentioning

confidence: 99%

Hypouricemic Effects of Chrysanthemum indicum L. and Cornus officinalis on Hyperuricemia-Induced HepG2 Cells, Renal Cells, and Mice

Kim

Yun

Lee

et al. 2021

Plants

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Hyperuricemia, abnormally excess accumulation of uric acid, is caused by an imbalance between the production and excretion of uric acid and is a major cause of gout. We compared the effects of extracts from Chrysanthemum indicum L. (Ci) and Cornus officinalis Siebold and Zucc. (Co) on hyperuricemia, both individually and in combination (FSU-CC), using hypoxanthine-treated human liver cancer (HepG2) cells, primary mouse renal proximal tubule cells, and potassium oxonate induced hyperuricemic mice. The Ci contained 7.62 mg/g luteolin and 0 mg/g loganin, Co contained 0 mg/g luteolin and 4.90 mg/g loganin, and FSH-CC contained 3.95 mg/g luteolin and 2.48 mg/g loganin. We found that treatment with Ci, Co, and FSU-CC suppressed the activity of xanthine oxidase and mRNA expression of xanthine dehydrogenase while inducing an increase in the expression levels of the organic anion transporter 1 (OAT1) and organic anion transporter 3 (OAT3) proteins and a decrease in the expression levels of glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1) proteins. Particularly, treatment and supplementation with FSU-CC showed stronger effects than those of supplementation with either Ci or Co alone. We observed that the excretion of creatinine and uric acid in the combination of Ci and Co was higher than that observed in their individual supplementations and was similar to that of the normal group. Therefore, our data suggest that a combination of Ci and Co may potentially be used for the development of effective natural anti-hyperuricemic functional foods.

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“…By definition, HU refers to when levels of serum UA exceed 7 mg/dl in men and 6 mg/dl in women (Desideri et al 2014;Huang et al 2017). XO suppression induced by allopurinol therapy may lead ultimately to reduced production and thus low serum level of urate (Chen et al 2016); however, UA status is mainly controlled by both its rates of production and renal excretion, and while other factors may contribute to a rise in UA level, majority of HU cases are caused by diminished UA kidney excretion (Liu et al 2021). In the current study, however, serum UA was non-significantly altered, and current study readings of UA approached the 6 mg/dl; thus as major contribution for maintaining UA level comes from renal excretion, rather than production, and unless renal function is overtly impaired, suppression of production (by the drug) should produce a minor effect, which we argue is the case in present study findings.…”

Section: Discussionmentioning

confidence: 99%

Biomarkers of iron status in allopurinol-treated renal stone patients

Zainal¹,

Faisal²,

Ahmad³

2021

PHAR

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Limited evidence exists on the effect of xanthine oxidase inhibitors in nephrolithiasis patients on iron status markers, beyond their effects on urate. The aim of this study was to investigate whether allopurinol therapy was associated with a significant impact on parameters related to iron status, in patients with renal stones. Allopurinol treatment was associated with a nonsignificant decline in serum uric acid. There were no significant differences in serum levels of transferrin and ferritin after treatment with allopurinol compared to pre-treatment levels. A non-significant fall in serum levels of haptoglobin was registered. The drug was associated with a significant rise in serum iron levels. Serum uric acid and iron did not show a significant correlation with any parameter in the study. Allopurinol exerted an overall non-significant effect on iron metabolism in nephrolithiasis patients, save for serum iron, this entails lack of untoward effects in populations with-iron related conditions.

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

Cited by 98 publications

References 159 publications

Antihyperuricemic Effect of Dendropanax morbifera Leaf Extract in Rodent Models

Antihyperuricemic Effect of Dendropanax morbifera Leaf Extract in Rodent Models

Hypouricemic Effects of Chrysanthemum indicum L. and Cornus officinalis on Hyperuricemia-Induced HepG2 Cells, Renal Cells, and Mice

Biomarkers of iron status in allopurinol-treated renal stone patients

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