Walter Mary F, Jacob Robert F, Day Charles A, Dahlborg Rachel, Weng Yujia, Mason R Preston
Elucida Research LLC, 100 Cummings Center, Suite 135L, Beverly, MA 01915, USA.
Atherosclerosis. 2004 Dec;177(2):235-43. doi: 10.1016/j.atherosclerosis.2004.10.001.
Clinical investigations have demonstrated a link between use of the sulfone cyclooxygenase-2 (COX-2) inhibitor, rofecoxib, and increased risk for atherothrombotic events. This increased risk was not observed for a sulfonamide COX-2 inhibitor (celecoxib), indicating a potential non-enzymatic mechanism for rofexocib. To test this hypothesis, we compared the independent effects of COX-2 inhibitors on human LDL oxidation, an important contributor to atherosclerotic cardiovascular disease. The results showed that rofecoxib (100 nM) significantly decreased (>40%, p<0.001) the lag time for LDL conjugated diene formation and increased levels of thiobarbituric-acid-reactive-substances (TBARS) in vitro. The pro-oxidant activity of rofecoxib was dose-dependent and attenuated by 70% (p<0.001) with the antioxidant, Trolox. Rofecoxib and etoricoxib (100 nM) also caused a marked increase (>35%, p<0.001) in non-enzymatic generation of isoprostanes, as measured by mass spectroscopy. Addition of rofecoxib to fresh human plasma reduced the oxygen radical antioxidant capacity (ORAC) by 34% (p<0.0001). By contrast, other selective (celecoxib, valdecoxib, meloxicam) and non-selective COX inhibitors (ibuprofen, naproxen, diclofenac) had no significant effect on LDL oxidation rates or plasma ORAC values, even at suprapharmacologic levels. X-ray diffraction analysis showed that sulfone COX-2 inhibitors interact differently with membrane phospholipids, suggesting a physico-chemical basis for the pro-oxidant activity. These results demonstrate that sulfone COX-2 inhibitors increase the susceptibility of biological lipids to oxidative modification through a non-enzymatic process. These findings may provide mechanistic insight into reported differences in cardiovascular risk for COX-2 inhibitors.
临床研究表明，使用磺酰基环氧化酶-2（COX-2）抑制剂罗非昔布与动脉粥样硬化血栓形成事件风险增加之间存在关联。对于磺酰胺类COX-2抑制剂（塞来昔布），未观察到这种风险增加，这表明罗非昔布存在潜在的非酶促机制。为了验证这一假设，我们比较了COX-2抑制剂对人低密度脂蛋白（LDL）氧化的独立影响，LDL氧化是动脉粥样硬化性心血管疾病的一个重要促成因素。结果显示，罗非昔布（100 nM）在体外显著缩短（>40%，p<0.001）了LDL共轭二烯形成的延迟时间，并增加了硫代巴比妥酸反应性物质（TBARS）的水平。罗非昔布的促氧化活性呈剂量依赖性，抗氧化剂托可索仑可使其降低70%（p<0.001）。通过质谱测定，罗非昔布和依托考昔（100 nM）还显著增加（>35%，p<0.001）了异前列腺素的非酶促生成。向新鲜人血浆中添加罗非昔布可使氧自由基抗氧化能力（ORAC）降低34%（p<0.0001）。相比之下，其他选择性（塞来昔布、伐地昔布、美洛昔康）和非选择性COX抑制剂（布洛芬、萘普生、双氯芬酸）即使在超药理水平下，对LDL氧化速率或血浆ORAC值也没有显著影响。X射线衍射分析表明，磺酰基COX-2抑制剂与膜磷脂的相互作用不同，这为促氧化活性提供了物理化学基础。这些结果表明，磺酰基COX-2抑制剂通过非酶促过程增加了生物脂质对氧化修饰的敏感性。这些发现可能为COX-2抑制剂心血管风险差异的报道提供机制上的见解。
