Pommery J, Pommery N, Hénichart J-P
Institut de Chimie Pharmaceutique Albert Lespagnol, EA 2692, Lille, France.
Prostaglandins Leukot Essent Fatty Acids. 2005 Dec;73(6):411-7. doi: 10.1016/j.plefa.2005.08.009. Epub 2005 Oct 6.
The arachidonic acid metabolizing enzymes, the cyclooxygenases (COXs) and lipoxygenases (LOXs), have been implicated in the development of a variety of cancers and numerous new therapeutic inhibitors are currently under investigation. However, given the interdependence of the two pathways, the effect of inhibiting one pathway with relatively selective agents can only be appreciated in the in vivo situation. Clearly then, because of their potential beneficial or deleterious effects, it is important to understand the nature and levels of the resulting arachidonic acid metabolites when treating patients with relatively selective inhibitor drugs. In this study, using reference COX-2, 5-LOX and dual COX-2/5-LOX inhibitors, we devised a protocol which permitted the simultaneous quantification of eicosanoid metabolites formed during stimulation of human peripheral venous blood samples with the calcium ionophore, A23187, in the absence and presence of lipopolysaccharide (LPS). Not surprisingly, the end products of both COX and LOX pathways were affected depending on the inhibitor, or combination of inhibitors, used and the concentrations of drug tested. In conclusion, the method described permits the rapid screening of novel compounds for potentially positive and/or negative effects upon the products of arachidonic acid metabolism.
花生四烯酸代谢酶，即环氧化酶（COXs）和脂氧合酶（LOXs），与多种癌症的发生发展有关，目前有许多新型治疗抑制剂正在研究中。然而，鉴于这两条途径的相互依赖性，只有在体内情况下才能了解用相对选择性的药物抑制一条途径的效果。显然，由于它们可能产生有益或有害的影响，在用相对选择性的抑制剂药物治疗患者时，了解由此产生的花生四烯酸代谢产物的性质和水平非常重要。在本研究中，我们使用参考COX-2、5-LOX和双重COX-2/5-LOX抑制剂，设计了一种方案，该方案允许在不存在和存在脂多糖（LPS）的情况下，同时定量在用钙离子载体A23187刺激人外周静脉血样本过程中形成的类花生酸代谢产物。不出所料，COX和LOX途径的终产物受到所用抑制剂或抑制剂组合以及测试药物浓度的影响。总之，所描述的方法允许快速筛选新型化合物对花生四烯酸代谢产物的潜在正面和/或负面影响。
