Direct Radical Scavenging Activity of Benzbromarone Provides Beneficial Antioxidant Properties for Hyperuricemia Treatment
Direct Radical Scavenging Activity of Benzbromarone Provides Beneficial Antioxidant Properties for Hyperuricemia Treatment
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DOI：
10.1248/bpb.b14-00514
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发表时间：
2015-03-01
影响因子：
2
通讯作者：
Hirata, Sumio
中科院分区：
文献类型：
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作者：
Kadowaki, Daisuke;Sakaguchi, Shoichi;Hirata, Sumio
尿酸在生理条件下对外界氧化应激具有重要的抗氧化作用。然而，尿酸本身可以通过减少脂肪细胞和血管细胞中烟酰胺腺嘌呤二核苷酸磷酸(NADPH)氧化酶的激活来增加氧化应激。尿酸转运蛋白1参与了这种氧化应激的产生。此外，尿酸局部激活肾素血管紧张素系统，从而产生血管紧张素II，从而增加细胞内的氧化应激。已有报道苯溴马龙通过抑制尿酸转运体1抑制肾小管上皮细胞尿酸重吸收。在本研究中，我们从多个角度评价了苯溴马龙的体外抗氧化作用。首先，用化学发光法和电子顺磁共振技术测定了苯溴马龙对自由基的直接捕获能力。其次，利用内皮细胞评价苯溴马龙对高尿酸血症大鼠细胞内抗氧化活性的影响。根据这些结果，推测苯溴马龙可直接清除超氧阴离子自由基。此外，苯溴马龙还可抑制血管紧张素II或尿酸诱导的内皮细胞内活性氧的产生。这些发现表明，苯溴马龙具有直接清除自由基的能力，并可能在血液中达到治疗水平的水平上作为抗氧化剂，对抗尿酸和血管紧张素II诱导的内皮细胞氧化应激。
Uric acid exerts an important antioxidant effect against external oxidative stress under physiological conditions. However, uric acid itself can increase oxidative stress via reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation in adipocytes and vascular cells. Uric acid transporter 1 is involved in the generation of this oxidative stress. Furthermore, uric acid locally activates the renin angiotensin system, thus producing angiotensin II and subsequently increasing intracellular oxidative stress. Benzbromarone has been reported to suppress uric acid reabsorption via uric acid transporter 1 inhibition in renal tubular cells. In this study we evaluated the in vitro antioxidant effect of benzbromarone from several perspectives. First, the direct radical-trapping capacity of benzbromarone was measured by chemiluminescence assay and electron paramagnetic resonance spectroscopy. Second, the intracellular antioxidant activity of benzbromarone in hyperuricemia was evaluated using endothelial cells. In light of these results, benzbromarone is hypothesized directly to scavenge the superoxide anion radical. In addition, benzbromarone inhibited reactive oxygen species production that was induced by angiotensin II or uric acid in endothelial cells. These findings suggest that benzbromarone possesses the ability directly to scavenge radicals and may act as an antioxidant against uric acid and angiotensin II-induced oxidative stresses in endothelial cells at therapeutically achievable levels in blood.