Kadowaki Daisuke, Sakaguchi Shoichi, Miyamoto Yohei, Taguchi Kazuaki, Muraya Nanako, Narita Yuki, Sato Keizo, Chuang Victor Tuan Giam, Maruyama Toru, Otagiri Masaki, Hirata Sumio
Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Kumamoto University; Center for Clinical Pharmaceutical Sciences, 5-1 Oe-honmachi, Chuo-ku 862-0973, Japan.
Biol Pharm Bull. 2015;38(3):487-92. doi: 10.1248/bpb.b14-00514. Epub 2015 Jan 15.
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.
在生理条件下，尿酸对外部氧化应激发挥着重要的抗氧化作用。然而，尿酸本身可通过激活脂肪细胞和血管细胞中的还原型烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶来增加氧化应激。尿酸转运蛋白1参与了这种氧化应激的产生。此外，尿酸可局部激活肾素-血管紧张素系统，从而产生血管紧张素II，随后增加细胞内氧化应激。据报道，苯溴马隆可通过抑制肾小管细胞中的尿酸转运蛋白1来抑制尿酸重吸收。在本研究中，我们从多个角度评估了苯溴马隆的体外抗氧化作用。首先，通过化学发光分析和电子顺磁共振光谱法测定苯溴马隆的直接自由基捕获能力。其次，使用内皮细胞评估苯溴马隆在高尿酸血症中的细胞内抗氧化活性。鉴于这些结果，推测苯溴马隆可直接清除超氧阴离子自由基。此外，苯溴马隆可抑制内皮细胞中由血管紧张素II或尿酸诱导的活性氧生成。这些发现表明，苯溴马隆具有直接清除自由基的能力，并且在血液中可达到的治疗水平下，可能作为一种抗氧化剂抵抗尿酸和血管紧张素II诱导的内皮细胞氧化应激。
