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.

Podocyte Injury and Albuminuria in Experimental Hyperuricemic Model Rats

“…On the other hand, UA loses its radical scavenging activity under hydrophobic conditions [44] and can become a strong prooxidant within the cells. Indeed, recent studies indicate that UA once enters into intracellular compartment increases reactive oxygen species [21, 45, 46]. Consistent with these data, we found that hyperuricemia caused glomerular injury, which was associated with increased 8OHdG levels.…”

Randomized, Open-Label, Cross-Over Comparison of the Effects of Benzbromarone and Febuxostat on Endothelial Function in Patients with Hyperuricemia

“…Kadowaki possess direct scavenging ability against O2 − and LOO and suppress ROS production induced by uric acid and angiotensin II in vascular endothelial cells. 21) These findings suggested that benzbromarone reduces ROS production directly and indirectly by acting as both a URAT1 inhibitor and a radical scavenger, respectively. 21) On the other hand, allopurinol inhibits ROS production via XO inhibition, but it does not act as a radical scavenger.…”

Association between Dietary Zinc Intake and Hyperuricemia among Adults in the United States

“…In addition, uric acid plays an important role in the pathogenesis of reactive oxygen species-related diseases [ 35 ], uric acid has been reported to stimulate increases nicotinamide adenine dinucleotide phosphate oxidase-derived reactive oxygen species production in adipocytes, vascular smooth muscle cells, as well as vascular endothelial cells [ 36 , 37 ]. Furthermore, uric acid may function as a pro-oxidant in HU, despite acting as an antioxidant under physiological conditions [ 38 ]. From the above analysis, it is speculated that dietary zinc intake maybe negatively associated with HU through the antioxidant properties.…”