Allopurinol is a pyrazolopyrimidine xanthine oxidase inhibitor with IC50 of 7.82±0.12μM. Allopurinol inhibits xanthine oxidase (XO)-mediated oxidation of hypoxanthine and xanthine, thereby reducing uric acid and reactive oxygen species production; its active metabolite oxypurinol prolongs XO inhibition. Allopurinol is used in research on purine metabolism, hyperuricemia, gout, oxidative stress, cardiovascular remodeling, bone formation, hypoxic signaling, and kidney injury.
In vitro, Allopurinol (10μg/mL, 100μg/mL, and 1000μg/mL; 17h) reduced hypoxia-inducible factor 1 alpha (HIF-1α) and HIF-2α protein accumulation in human foreskin fibroblasts at the highest concentration without increasing cleaved poly(ADP-ribose) polymerase; Allopurinol (0μg/mL, 10μg/mL, 100μg/mL, and 1000μg/mL; 24h) progressively shortened endothelial tube length in human umbilical vein endothelial cells[1]. Allopurinol (0.1μM and 1μM; 7 or 14 days) reduced XO activity by up to 30% in primary rat calvarial osteoblasts, increased bone formation by approximately fourfold, increased tissue-nonspecific alkaline phosphatase activity, increased osteocalcin and alkaline phosphatase mRNA expression, and reduced ectonucleotide pyrophosphatase/phosphodiesterase 1 expression[2]. Allopurinol (250μM) reduced the increases in xanthine oxidase (XO) activity and mitochondrial swelling induced by 3h of cyclic stretch in primary rat ventricular cardiomyocytes[3].
In vivo, Allopurinol (100mg/kg/day; administered in drinking water daily for 4 weeks beginning 1 week after streptozotocin induction) increased cardiac Nrf2, HO-1, and p62, reduced myocardial oxidative stress, apoptosis, and autophagy, and improved heart rate, left ventricular ejection fraction, stroke work, and cardiac output in type 1 diabetic rats[4]. Allopurinol (200mg/kg; oral administration at 24h and 1h before coronary occlusion) reduced ventricular fibrillation incidence from 67% to 11% and decreased mortality in anesthetized rats subjected to coronary ischemia and reperfusion[5]. Allopurinol (5mg/kg; oral administration once daily for 7 days, 1h after 250mg/kg potassium oxonate intraperitoneal injection) reduced serum uric acid, blood urea nitrogen, serum and hepatic XO activity, malondialdehyde, interleukin 1 beta, and tumor necrosis factor alpha, regulated renal urate-transporter expression, and improved glomerular and tubular architecture in hyperuricemic Swiss mice[6]. Allopurinol (300mg/L; continuous administration in drinking water for 7 days before 0.25mg/kg Bothrops jararaca venom intravenous infusion) increased inulin clearance, renal blood flow, and serum glutathione and reduced renal vascular resistance, plasma and renal nitrotyrosine, and acute kidney injury in Wistar rats[7].
References:[1] Sun Y, George J, Rocha S. Dose-dependent effects of allopurinol on human foreskin fibroblast cells and human umbilical vein endothelial cells under hypoxia. PLoS One. 2015;10(4):e0123649. doi:10.1371/journal.pone.0123649.
[2] Orriss IR, Arnett TR, George J, Witham MD. Allopurinol and oxypurinol promote osteoblast differentiation and increase bone formation. Exp Cell Res. 2016;342(2):166-174. doi:10.1016/j.yexcr.2016.03.004.
[3] Gladden JD, Zelickson BR, Wei CC, Ulasova E, Zheng J, Ahmed MI, et al. Novel insights into interactions between mitochondria and xanthine oxidase in acute cardiac volume overload. Free Radic Biol Med. 2011;51(11):1975-1984. doi:10.1016/j.freeradbiomed.2011.08.022.
[4] Luo J, Yan D, Li S, Liu S, Zeng F, Cheung CW, et al. Allopurinol reduces oxidative stress and activates Nrf2/p62 to attenuate diabetic cardiomyopathy in rats. J Cell Mol Med. 2020;24(2):1760-1773. doi:10.1111/jcmm.14870.
[5] Manning AS, Coltart DJ, Hearse DJ. Ischemia and reperfusion-induced arrhythmias in the rat: effects of xanthine oxidase inhibition with allopurinol. Circ Res. 1984;55(4):545-548. doi:10.1161/01.RES.55.4.545.
[6] Alghamdi YS, Soliman MM, Nassan MA. Impact of lesinurad and allopurinol on experimental hyperuricemia in mice: biochemical, molecular and immunohistochemical study. BMC Pharmacol Toxicol. 2020;21:10. doi:10.1186/s40360-020-0386-7.
[7] Gois PHF, Martines MS, Ferreira D, Volpini R, Canale D, Malaque C, et al. Allopurinol attenuates acute kidney injury following Bothrops jararaca envenomation. PLoS Negl Trop Dis. 2017;11(11):e0006024. doi:10.1371/journal.pntd.0006024.