Department of Biology, The University of North Carolina at Chapel Hill, Chapel Hill, NC; and.
Research Center for Integrative Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
Blood. 2020 Aug 13;136(7):898-908. doi: 10.1182/blood.2019004234.
Drug-induced bleeding disorders contribute to substantial morbidity and mortality. Antithrombotic agents that cause unintended bleeding of obvious cause are relatively easy to control. However, the mechanisms of most drug-induced bleeding disorders are poorly understood, which makes intervention more difficult. As most bleeding disorders are associated with the dysfunction of coagulation factors, we adapted our recently established cell-based assay to identify drugs that affect the biosynthesis of active vitamin K-dependent (VKD) coagulation factors with possible adverse off-target results. The National Institutes of Health (NIH) Clinical Collection (NCC) library containing 727 drugs was screened, and 9 drugs were identified, including the most commonly prescribed anticoagulant warfarin. Bleeding complications associated with most of these drugs have been clinically reported, but the pathogenic mechanisms remain unclear. Further characterization of the 9 top-hit drugs on the inhibition of VKD carboxylation suggests that warfarin, lansoprazole, and nitazoxanide mainly target vitamin K epoxide reductase (VKOR), whereas idebenone, clofazimine, and AM404 mainly target vitamin K reductase (VKR) in vitamin K redox cycling. The other 3 drugs mainly affect vitamin K availability within the cells. The molecular mechanisms underlying the inactivation of VKOR and VKR by these drugs are clarified. Results from both cell-based and animal model studies suggest that the anticoagulation effect of drugs that target VKOR, but not VKR, can be rescued by the administration of vitamin K. These findings provide insights into the prevention and management of drug-induced bleeding disorders. The established cell-based, high-throughput screening approach provides a powerful tool for identifying new vitamin K antagonists that function as anticoagulants.
药物诱导的出血性疾病会导致严重的发病率和死亡率。引起明显原因的意外出血的抗血栓药物相对容易控制。然而，大多数药物诱导的出血性疾病的机制尚未得到很好的理解，这使得干预更加困难。由于大多数出血性疾病与凝血因子的功能障碍有关，我们采用了最近建立的基于细胞的检测方法来识别可能具有不良的非靶向作用结果的影响活性维生素 K 依赖性（VKD）凝血因子生物合成的药物。筛选了包含 727 种药物的美国国立卫生研究院（NIH）临床收藏（NCC）库，发现了 9 种药物，包括最常用的抗凝药华法林。这些药物中的大多数都与出血并发症有关，但其发病机制尚不清楚。进一步对 9 种抑制 VKD 羧化作用的顶级药物进行特征描述表明，华法林、兰索拉唑和硝唑尼特主要靶向维生素 K 环氧化物还原酶（VKOR），而艾地苯醌、氯法齐明和 AM404 主要靶向维生素 K 还原酶（VKR）在维生素 K 氧化还原循环中。另外 3 种药物主要影响细胞内维生素 K 的可用性。阐明了这些药物对 VKOR 和 VKR 的失活的分子机制。细胞基础和动物模型研究的结果表明，靶向 VKOR 而不是 VKR 的药物的抗凝作用可以通过给予维生素 K 来挽救。这些发现为预防和管理药物诱导的出血性疾病提供了思路。所建立的基于细胞的高通量筛选方法为识别作为抗凝剂的新型维生素 K 拮抗剂提供了有力的工具。
