Metabolic profiling of murine plasma reveals an unexpected biomarker in rofecoxib-mediated cardiovascular events
Metabolic profiling of murine plasma reveals an unexpected biomarker in rofecoxib-mediated cardiovascular events
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DOI：
10.1073/pnas.1011278107
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发表时间：
2010-09-28
影响因子：
11.1
通讯作者：
Hammock, Bruce D.
中科院分区：
文献类型：
--
作者：
Liu, Jun-Yan;Li, Ning;Hammock, Bruce D.
长期服用高水平的选择性 COX-2 抑制剂 (coxib)，特别是罗非考昔、伐地考昔和帕瑞考昔，会增加心血管疾病的风险。了解这些不良心血管事件可能存在的多种机制对于评估考昔布的风险和益处以及开发更安全的考昔布至关重要。目前对这些机制的理解可能还不完整。使用代谢组学方法，我们证明口服罗非昔布 3 个月会导致 20-羟基二十碳四烯酸 (20-HETE) 的血液水平升高 120 倍以上，这与小鼠模型中尾部出血时间显着缩短相关。我们测试了以下假设：20-HETE 的这种急剧增加归因于其代谢的抑制，并且罗非考昔给药后出血时间的缩短部分归因于这种增加。 SC。输注20-HETE可显着缩短尾部出血时间。给予罗非昔布后，20-HETE 生物合成和细胞色素 P4A 样免疫反应性均未增加，但添加考昔布后，体外 20-HETE 产量增加。 20-HETE 在缩短体外凝血时间方面比其 COX 介导的代谢物更有效。此外，20-HETE（而不是罗非昔布）在体外以剂量依赖性方式显着增加大鼠血小板聚集。这些数据表明 20-HETE 作为罗非考昔暴露的标志物，罗非考昔对 20-HETE 降解的抑制是其急剧增加、出血时间缩短以及可能与罗非考昔相关的不良心血管事件的部分解释。
Chronic administration of high levels of selective COX-2 inhibitors (coxibs), particularly rofecoxib, valdecoxib, and parecoxib, increases risk for cardiovascular disease. Understanding the possibly multiple mechanisms underlying these adverse cardiovascular events is critical for evaluating the risks and benefits of coxibs and for development of safer coxibs. The current understanding of these mechanisms is likely incomplete. Using a metabolomics approach, we demonstrate that oral administration of rofecoxib for 3 mo results in a greater than 120-fold higher blood level of 20-hydroxyeicosatetraenoic acid (20-HETE), which correlates with a significantly shorter tail bleeding time in a murine model. We tested the hypothesis that this dramatic increase in 20-HETE is attributable to inhibition of its metabolism and that the shortened bleeding time following rofecoxib administration is attributable, in part, to this increase. The s.c. infusion of 20-HETE shortened the tail bleeding time dramatically. Neither 20-HETE biosynthesis nor cytochrome P4A-like immune reactivity was increased by rofecoxib administration, but 20-HETE production increased in vitro with the addition of coxib. 20-HETE is significantly more potent than its COX-mediated metabolites in shortening clotting time in vitro. Furthermore, 20-HETE but not rofecoxib significantly increases rat platelet aggregation in vitro in a dose-dependent manner. These data suggest 20-HETE as a marker of rofecoxib exposure and that inhibition of 20-HETE's degradation by rofecoxib is a partial explanation for its dramatic increase, the shortened bleeding time, and, possibly, the adverse cardiovascular events associated with rofecoxib.