Febuxostat is a potent, selective, non-purine inhibitor of xanthine oxidase (XO) and xanthine dehydrogenase (XDH), with an inhibition constant (Ki) of 0.6nM against XO[1]. Febuxostat binds the molybdenum-pterin center of oxidized and reduced xanthine oxidoreductase (XOR), suppressing hypoxanthine-to-xanthine and xanthine-to-uric-acid conversion and reducing endothelial-bound XOR-derived reactive oxygen species (ROS)[1,4]. Febuxostat is used in research on purine and urate metabolism, macrophage inflammation, endothelial oxidative injury, atherosclerosis, and hyperuricemia-associated cardiorenal injury[1-7].
In vitro, Febuxostat (30μM; 10min pretreatment followed by 100ng/mL lipopolysaccharide for 20h) reduced monocyte chemoattractant protein-1 (MCP-1) production in phorbol 12-myristate 13-acetate-differentiated THP-1 macrophages, increased mitogen-activated protein kinase phosphatase-1 (MKP-1) activity, and reduced c-Jun N-terminal kinase (JNK) phosphorylation[2]. Febuxostat (200μM; 30min pretreatment followed by 2.5μM nigericin or 0.25mg/mL monosodium urate crystals for 2h) reduced interleukin-1β (IL-1β) secretion and cell death in murine bone-marrow-derived macrophages and preserved intracellular adenosine triphosphate (ATP) and mitochondrial membrane potential[5]. Febuxostat (5μM and 10μM; 6h) reduced oxidized low-density lipoprotein-induced mitochondrial ROS production, cellular injury, and monocyte attachment in human aortic valve endothelial cells[6].
In vivo, Febuxostat (2.5mg/kg/day; oral intake in drinking water once daily for 12 weeks) reduced aortic plaque area and arterial ROS, decreased aortic MCP-1 expression, and improved endothelial-dependent relaxation in apolipoprotein E-deficient (ApoE-/-) mice fed a high-cholesterol diet[3]. Febuxostat (approximately 3mg/kg/day; oral intake in drinking water once daily for 8 weeks) reduced serum uric acid and proteinuria, attenuated glomerular, tubulointerstitial, and renal arteriolar injury, and reduced cardiac hypertrophy and fibrosis in hyperuricemic 5/6-nephrectomized Sprague-Dawley rats[7].
References:[1] Takano Y, Hase-Aoki K, Horiuchi H, Zhao L, Kasahara Y, Kondo S, et al. Selectivity of febuxostat, a novel non-purine inhibitor of xanthine oxidase/xanthine dehydrogenase. Life Sci. 2005;76(16):1835-1847. doi:10.1016/j.lfs.2004.10.031.
[2] Nomura J, Busso N, Ives A, Tsujimoto S, Tamura M, So A, et al. Febuxostat, an inhibitor of xanthine oxidase, suppresses lipopolysaccharide-induced MCP-1 production via MAPK phosphatase-1-mediated inactivation of JNK. PLoS One. 2013;8(9):e75527. doi:10.1371/journal.pone.0075527.
[3] Nomura J, Busso N, Ives A, Matsui C, Tsujimoto S, Shirakura T, et al. Xanthine oxidase inhibition by febuxostat attenuates experimental atherosclerosis in mice. Sci Rep. 2014;4:4554. doi:10.1038/srep04554.
[4] Malik UZ, Hundley NJ, Romero G, Radi R, Freeman BA, Tarpey MM, et al. Febuxostat inhibition of endothelial-bound XO: implications for targeting vascular ROS production. Free Radic Biol Med. 2011;51(1):179-184. doi:10.1016/j.freeradbiomed.2011.04.004.
[5] Nomura J, Kobayashi T, So A, Busso N. Febuxostat, a xanthine oxidoreductase inhibitor, decreases NLRP3-dependent inflammation in macrophages by activating the purine salvage pathway and restoring cellular bioenergetics. Sci Rep. 2019;9:17314. doi:10.1038/s41598-019-53965-x.
[6] Liang X, Li P, Xie W, Lin Z, Wang Z, Zeng S, et al. Febuxostat protects human aortic valve endothelial cells from oxidized low-density lipoprotein-induced injury and monocyte attachment. J Cardiovasc Pharmacol. 2022;80(6):861-868. doi:10.1097/FJC.0000000000001326.
[7] Omizo H, Tamura Y, Morimoto C, Ueno M, Hayama Y, Kuribayashi-Okuma E, et al. Cardio-renal protective effect of the xanthine oxidase inhibitor febuxostat in the 5/6 nephrectomy model with hyperuricemia. Sci Rep. 2020;10:9326. doi:10.1038/s41598-020-65706-6.