Bilirubin, a yellow breakdown product of heme catabolism, inhibits the cleavage of F485-rVWF73-H, D633-rVWF73-H, and GST-rVWF71-11K by ADAMTS13, with the IC50 values of 13μM, 70μM, and 17μM, respectively[1]. Bilirubin is the ultimate breakdown product of haemoglobin and serves as a diagnostic marker of liver and blood disorders[2].
In vitro, Bilirubin treatment at 0.4μM for 24h significantly restored cell viability in both hypoxic (5% O2) and hyperoxic (80% O2) conditions and attenuated oxidative stress-induced responses in rat type II alveolar cells[3]. Treatment of rat hepatic stellate cells with 20mg/L bilirubin for 24 hours significantly inhibited cell viability, decreased the protein expression level of α-smooth muscle actin, and promoted cell apoptosis[4]. Bilirubin treatment at 600μM for 20 min significantly attenuated the bactericidal activity of E. coli in isolated human neutrophils[5].
In vivo, Bilirubin treatment via twice daily intraperitoneal injections at 25mg/kg for 10 days can effectively inhibit tumor growth and prolong the survival time of the mice 14 days after the establishment of the transplanted tumor model[6]. Sprague Dawley rats were intravenously injected with 60mg/kg Bilirubin within 5min, the hippocampal CA3 region of rats showed prolongation of peak latencies and a decrease of slopes of the evoked potentials[7]. Bilirubin treatment (100 mg/kg twice daily; i.p.) for two weeks effectively suppressed experimental autoimmune encephalomyelitis in SJL/J mice[8].
References:
[1] Lu R N, Yang S, Wu H M, et al. Unconjugated bilirubin inhibits proteolytic cleavage of von Willebrand factor by ADAMTS13 protease[J]. Journal of Thrombosis and Haemostasis, 2015, 13(6): 1064-1072.
[2] Fevery J. Bilirubin in clinical practice: a review[J]. Liver International, 2008, 28(5): 592-605.
[3] Endesfelder S, Schmitz T, Bührer C. Bilirubin Exerts Protective Effects on Alveolar Type II Pneumocytes in an In Vitro Model of Oxidative Stress[J]. International Journal of Molecular Sciences, 2024, 25(10): 5323.
[4] Tang Y, Zhang Q, Zhu Y, et al. Low concentrations of bilirubin inhibit activation of hepatic stellate cells in vitro[J]. Molecular Medicine Reports, 2017, 15(4): 1647-1653.
[5] Arai T, Yoshikai Y, Kamiya J, et al. Bilirubin impairs bactericidal activity of neutrophils through an antioxidant mechanism in vitro[J]. Journal of Surgical Research, 2001, 96(1): 107-113.
[6] Ollinger R, Kogler P, Troppmair J, et al. Bilirubin inhibits tumor cell growth via activation of ERK[J]. Cell Cycle, 2007, 6(24): 3078-3085.
[7] Zhang L, Liu W, Tanswell A K, et al. The effects of bilirubin on evoked potentials and long-term potentiation in rat hippocampus in vivo[J]. Pediatric research, 2003, 53(6): 939-944.
[8] Liu Y, Li P, Lu J, et al. Bilirubin possesses powerful immunomodulatory activity and suppresses experimental autoimmune encephalomyelitis[J]. The Journal of Immunology, 2008, 181(3): 1887-1897.
Bilirubin是血红素分解代谢产生的黄色终产物，可抑制ADAMTS13对F485-rVWF73-H、D633-rVWF73-H和GST-rVWF71-11K的切割活性，IC50值分别为13μM、70μM和17μM[1]。作为血红蛋白的最终分解产物，Bilirubin是肝脏和血液疾病的诊断标志物[2]。
在体外，0.4μM的Bilirubin处理24小时能显著恢复大鼠II型肺泡细胞在低氧（5% O2）和高氧（80% O2）条件下的细胞活力，并减轻氧化应激反应[3]。20mg/L的Bilirubin处理大鼠肝星状细胞24小时可显著抑制细胞活力、降低α-平滑肌肌动蛋白表达并促进细胞凋亡[4]。600μM的Bilirubin处理20分钟会显著减弱分离的人中性粒细胞对大肠杆菌的杀菌活性[5]。
在体内，移植瘤模型小鼠经腹腔注射Bilirubin（25mg/kg，每日两次，持续10天）可有效抑制肿瘤生长并延长生存期[6]。Sprague Dawley大鼠静脉注射60mg/kg剂量的Bilirubin（5分钟内完成）后，海马CA3区诱发电位的峰值潜伏期延长且斜率下降[7]。SJL/J小鼠经腹腔注射Bilirubin（100mg/kg，每日两次，持续两周）可有效抑制实验性自身免疫性脑脊髓炎的发展[8]。