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New insights into purine metabolism in metabolic diseases: role of xanthine oxidoreductase activity.
American Journal of Physiology-Endocrinology and Metabolism ( IF 5.1 ) Pub Date : 2020-09-07 , DOI: 10.1152/ajpendo.00378.2020
Masato Furuhashi 1
Affiliation  

Xanthine oxidoreductase (XOR) consists of two different forms, xanthine dehydrogenase (XDH) and xanthine oxidase (XO), and is a rate-limiting enzyme of uric acid production from hypoxanthine and xanthine. Uric acid is the end-product of purine metabolism in humans and has a powerful antioxidant effect. The lack of ascorbic acid, known as vitamin C, in hominoids has been thought to cause a compensatory increase in uric acid as an antioxidant by unfunctional gene mutation of uricase to a pseudogene. Since XO is involved in an increase in reactive oxygen species (ROS) by generating superoxide and hydrogen peroxide, inadequate activation of XOR promotes oxidative stress-related tissue injury. Plasma XOR activity is associated with obesity, smoking, liver dysfunction, hyperuricemia, dyslipidemia, insulin resistance and adipokines, indicating a novel biomarker of metabolic disorders. However, XOR activity in adipose tissue is low in humans unlike in rodents, and hypoxanthine is secreted from human adipose tissue. The concentration of hypoxanthine, but not xanthine, is independently associated with obesity in a general population, indicating differential regulation of hypoxanthine and xanthine. Treatment with an XOR inhibitor can decrease uric acid for preventing gout, reduce production of XO-related ROS and promote reutilization of hypoxanthine and ATP production through the salvage pathway. It has recently been suggested that discontinuation of an XOR inhibitor causes adverse cardiovascular outcomes as XOR inhibitor withdrawal syndrome, possibly due to cardiac disturbance of conduction and contraction by reduced ATP production. New insights into purine metabolism including the role of XOR activity are discussed in this review.

中文翻译:

嘌呤在代谢疾病中代谢的新见解:黄嘌呤氧化还原酶活性的作用。

黄嘌呤氧化还原酶(XOR)由两种不同的形式组成:黄嘌呤脱氢酶(XDH)和黄嘌呤氧化酶(XO),并且是次黄嘌呤和黄嘌呤产生尿酸的限速酶。尿酸是人类嘌呤代谢的最终产物,具有强大的抗氧化作用。人们认为类人猿中缺乏抗坏血酸(称为维生素C)会通过尿酸酶的无效基因突变为假基因而导致尿酸作为抗氧化剂的代偿性增加。由于XO通过产生超氧化物和过氧化氢而导致活性氧(ROS)的增加,因此XOR活化不足会促进与氧化应激相关的组织损伤。血浆XOR活性与肥胖,吸烟,肝功能异常,高尿酸血症,血脂异常,胰岛素抵抗和脂肪因子有关,表明新陈代谢障碍的生物标志物。然而,与啮齿类动物不同,人在脂肪组织中的XOR活性较低,次黄嘌呤是人脂肪组织分泌的。在一般人群中,次黄嘌呤而不是黄嘌呤的浓度与肥胖症独立相关,表明次黄嘌呤和黄嘌呤的差异调节。用XOR抑制剂治疗可以减少尿酸以预防痛风,减少XO相关ROS的产生,并通过挽救途径促进次黄嘌呤和ATP产生的再利用。最近有人提出,停用XOR抑制剂会导致不良的心血管结果,如XOR抑制剂戒断综合征,这可能是由于ATP生成减少导致心脏传导和收缩受到干扰。
更新日期:2020-09-08
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