Add time:08/23/2019         Source:sciencedirect.com

Hyperuricemia is a kind of metabolic disease resulted from imbalance between urate production and excretion. Xanthine oxidase (XOD) or renal urate transporter 1 (URAT1) inhibitors have been applied for hyperuricemia treatment in clinic, but available drugs could not simultaneously target XOD and URAT1 and had various adverse effects. (E)-2-(4-bromophenyl)-1-(2, 4-dihydroxyphenyl)ethanone oxime (BDEO), as a deoxybenzoins oxime analog, was obtained from a cluster of deoxybenzoins derivatives synthesized by our research group with potent anti-hyperuricemic activity, which was expected to be dual inhibitor of XOD and URAT1. This study aimed to investigate effects of BDEO on XOD and URAT1 in vitro, as well as the possible mechanism by which BDEO attenuated hyperuricemia in vivo. In vitro, BDEO obviously inhibited XOD activity with an IC50 value of 3.33 μM, moreover, in Human embryonic kidney (HEK)293 cells expressing URAT1, BDEO and benzbromarone blocked uptake of uric acid with a Ki value of 0.145 μM. On the other hand, mice were orally administrated by oxonate for seven consecutive days to induce hyperuricemia, BDEO at various doses were administered intragastrically to hyperuricemic and normal mice daily. BDEO dose-dependently decreased serum urate level and uric acid excretion in 24 h in hyperuricemic mice. More importantly, BDEO significantly suppressed hepatic XOD activity and down-regulated renal URAT1 protein level in hyperuricemic mice. Notably, BDEO exhibited no effects on all these detected biochemical indicators in normal mice, predicting its safety. Taken together, the data suggested that BDEO may serve as a dual XOD and URAT1 inhibitor for treatment of hyperuricemia.

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