Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Pharmacogenomics J. 2011 Oct;11(5):337-47. doi: 10.1038/tpj.2010.49. Epub 2010 Jun 15.
The cyclooxygenase (COX) activity of prostaglandin H synthase-2 (PGHS-2) is implicated in colorectal cancer and is targeted by nonsteroidal anti-inflammatory drugs (NSAIDs) and dietary n-3 fatty acids. We used purified, recombinant proteins to evaluate the functional impacts of the R228H, E488G, V511A and G587R PGHS-2 polymorphisms on COX activity, fatty acid selectivity and NSAID actions. Compared to wild-type PGHS-2, COX activity with arachidonate was ∼20% lower in 488G and ∼20% higher in 511A. All variants showed time-dependent inhibition by the COX-2-specific inhibitor (coxib) nimesulide, but 488G and 511A had 30-60% higher residual COX activity; 511A also showed up to 70% higher residual activity with other time-dependent inhibitors. In addition, 488G and 511A differed significantly from wild type in Vmax values with the two fatty acids: 488G showed ∼20% less and 511A showed ∼20% more discrimination against eicosapentaenoic acid. The Vmax value for eicosapentaenoate was not affected in 228H or 587R, nor were the Km values or the COX activation efficiency (with arachidonate) significantly altered in any variant. Thus, the E488G and V511A PGHS-2 polymorphisms may predict who will most likely benefit from interventions with some NSAIDs or n-3 fatty acids.
前列腺素 H 合酶-2（PGHS-2）的环氧化酶（COX）活性与结直肠癌有关，其受到非甾体抗炎药（NSAIDs）和膳食 n-3 脂肪酸的靶向调控。我们使用纯化的重组蛋白来评估 R228H、E488G、V511A 和 G587R PGHS-2 多态性对 COX 活性、脂肪酸选择性和 NSAID 作用的功能影响。与野生型 PGHS-2 相比，488G 中花生四烯酸的 COX 活性降低了约 20%，511A 中的 COX 活性升高了约 20%。所有变体均表现出对 COX-2 特异性抑制剂（昔布）尼美舒利的时间依赖性抑制，但 488G 和 511A 具有 30-60%更高的残余 COX 活性；511A 对其他时间依赖性抑制剂的残余活性也高达 70%。此外，与野生型相比，488G 和 511A 在两种脂肪酸的 Vmax 值方面存在显著差异：488G 显示出对二十碳五烯酸的活性降低了约 20%，而 511A 则表现出对二十碳五烯酸的活性增加了约 20%。228H 或 587R 中，花生四烯酸的 Vmax 值不受影响，任何变体中，Km 值或 COX 激活效率（用花生四烯酸）也没有明显改变。因此，E488G 和 V511A PGHS-2 多态性可能预测哪些人最有可能受益于某些 NSAIDs 或 n-3 脂肪酸的干预。
