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.
|Original language||English (US)|
|Number of pages||9|
|State||Published - Dec 2004|
Bibliographical noteFunding Information:
The authors gratefully acknowledge the technical assistance of Drs. Russell Camp and Craig Story of Gordon College in Wenham MA. F 2 -Isoprostane levels were independently analyzed by the Antioxidant Research Laboratory of Tufts University, Boston, MA. RPM has received funding from National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH), the American Heart Association, and independent research grants and/or consulting fees from AstraZeneca, Bayer, Pfizer and Roche. All drugs were purchased from commercial sources by Elucida Research LLC (Beverly, MA), an independent research laboratory that provided funding for this work. No authors have direct financial relationships with any pharmaceutical company.
Copyright 2012 Elsevier B.V., All rights reserved.