title: Direct radical scavenging activity of benzbromarone provides beneficial antioxidant properties for hyperuricemia treatment.
abstract: 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.
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Kumamoto University; Center for Clinical Pharmaceutical Sciences, 5-1 Oe-honmachi, Chuo-ku 862-0973, Japan. d-kado@kumamoto-u.ac.jp
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kadowaki
authors.forename: Shoichi
authors.initials: S
authors.lastname: Sakaguchi
authors.forename: Yohei
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Taguchi
authors.forename: Nanako
authors.initials: N
authors.lastname: Muraya
authors.forename: Yuki
authors.initials: Y
authors.lastname: Narita
authors.forename: Keizo
authors.initials: K
authors.lastname: Sato
authors.forename: Victor Tuan Giam
authors.initials: VT
authors.lastname: Chuang
authors.forename: Toru
authors.initials: T
authors.lastname: Maruyama
authors.forename: Masaki
authors.initials: M
authors.lastname: Otagiri
authors.forename: Sumio
authors.initials: S
authors.lastname: Hirata
mesh_terms: D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D001553:Benzbromarone / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology / Q000627:therapeutic use; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D033461:Hyperuricemia / Q000097:blood / Q000188:drug therapy*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D014527:Uric Acid / Q000097:blood*
chemical_list: D000975:Antioxidants; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D013481:Superoxides; D014527:Uric Acid; D001553:Benzbromarone