Zileuton, a benzothiophene N-hydroxyurea, is an oral inhibitor of 5-Lipoxygenase[1]. Zileuton blocks 5-lipoxygenase activity to regulate leukotriene formation and reduces bronchial smooth-muscle tone[2]. Zileuton is a weak inhibitor of human liver microsomal CYP3A4, CYP2C9, and CYP2D6 activity, with IC50 >100μM [3]. Zileuton has been widely used in animal models to suppress inflammation and improve airway function[4].
In vitro, Zileuton treatment at 0.05μM Zileuton for 14 days reduced the content of neutral lipids and the release of interleukin-6 in human SZ95 sebocytes[5]. Treatment with 100µM Zileuton for 24h inhibited the lipopolysaccharide (LPS)-triggered increase in PGE2 production in mouse J774 macrophages without affecting cell viability[6]. Treatment with 50µM Zileuton for 1 hour significantly inhibited the proliferation and migration of human umbilical vein endothelial cells (HUVEC) induced by vascular endothelial growth factor (VEGF)[7].
In vivo, Zileuton treatment (50mg/kg; twice daily; p.o.) for 7 days alleviated colonic injury and decreased colonic myeloperoxidase (MPO) activity in an experimental model of rat colitis[8]. Oral administration of drinking water containing Zileuton (200mg/L) daily for 3 months can restore the memory impairment in aged mice with Alzheimer's disease and reverse the amyloid protein and tau pathological changes[9]. A single oral dose of Zileuton at 50mg/kg for 72 hours can inhibit neuronal apoptosis in rats after focal cerebral ischemia and alleviate brain damage[10].
References:
[1] Berger W, De Chandt M T M, Cairns C B. Zileuton: clinical implications of 5‐Lipoxygenase inhibition in severe airway disease[J]. International journal of clinical practice, 2007, 61(4): 663-676.
[2] Bell R L, Young P R, Albert D, et al. The discovery and development of zileuton: an orally active 5-lipoxygenase inhibitor[J]. International journal of immunopharmacology, 1992, 14(3): 505-510.
[3] Lu P, Schrag M L, Slaughter D E, et al. Mechanism-based inhibition of human liver microsomal cytochrome P450 1A2 by zileuton, a 5-lipoxygenase inhibitor[J]. Drug Metabolism and Disposition, 2003, 31(11): 1352-1360.
[4] Muthukrishnan P T, Nouraie M, Parikh A, et al. Zileuton use and phenotypic features in asthma[J]. Pulmonary Pharmacology & Therapeutics, 2020, 60: 101872.
[5] Zouboulis C C. Zileuton, a new efficient and safe systemic anti-acne drug[J]. Dermato-endocrinology, 2009, 1(3): 188-192.
[6] Rossi A, Pergola C, Koeberle A, et al. The 5-lipoxygenase inhibitor, zileuton, suppresses prostaglandin biosynthesis by inhibition of arachidonic acid release in macrophages[J]. British journal of pharmacology, 2010, 161(3): 555-570.
[7] Lim H J, Park J, Um J Y, et al. Zileuton, a 5-lipoxygenase inhibitor, exerts anti-angiogenic effect by inducing apoptosis of HUVEC via BK channel activation[J]. Cells, 2019, 8(10): 1182.
[8] Zingarelli B, Squadrito F, Graziani P, et al. Effects of zileuton, a new 5-lipoxygenase inhibitor, in experimentally induced colitis in rats[J]. Agents and actions, 1993, 39(3): 150-156.
[9] Di Meco A, Lauretti E, Vagnozzi A N, et al. Zileuton restores memory impairments and reverses amyloid and tau pathology in aged Alzheimer's disease mice[J]. Neurobiology of aging, 2014, 35(11): 2458-2464.
[10] Shi S, Yang W, Tu X, et al. 5-Lipoxygenase inhibitor zileuton inhibits neuronal apoptosis following focal cerebral ischemia[J]. Inflammation, 2013, 36(6): 1209-1217.
Zileuton是一种苯并噻吩N-羟基脲类化合物，作为口服5-脂氧合酶抑制剂[1]。Zileuton通过阻断5-脂氧合酶活性调节白三烯合成，降低支气管平滑肌张力[2]。Zileuton对人肝微粒体CYP3A4、CYP2C9和CYP2D6活性抑制较弱（IC50 >100μM）[3]。Zileuton已广泛应用于动物模型的炎症抑制和气道功能改善研究[4]。
在体外，0.05μM的Zileuton处理人SZ95皮脂腺细胞14天可减少中性脂质含量并降低白细胞介素-6释放[5]。100µM的Zileuton处理小鼠J774巨噬细胞24小时能抑制脂多糖（LPS）触发的PGE2产量增加且不影响细胞活力[6]。50µM的Zileuton处理人脐静脉内皮细胞（HUVEC）1小时可显著抑制血管内皮生长因子（VEGF）诱导的增殖与迁移[7]。
在体内，实验性结肠炎大鼠每日两次口服Zileuton（50mg/kg；持续7天）可减轻结肠损伤并降低结肠髓过氧化物酶（MPO）活性[8]。每日口服含Zileuton（200mg/L）的饮用水，连续3个月，可恢复老年阿尔茨海默病小鼠的记忆障碍，逆转淀粉样蛋白和tau的病理改变[9]。单次口服50mg/kg剂量的Zileuton（72小时）可抑制局灶性脑缺血后的大鼠神经元凋亡并减轻大鼠轻脑损伤[10]。