Sulfone COX-2 inhibitors increase susceptibility of human LDL and plasma to oxidative modification: comparison to sulfonamide COX-2 inhibitors and NSAIDs

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • Celecoxib
  • Cholesterol, LDL / metabolism*
  • Chromans / pharmacology
  • Cyclooxygenase Inhibitors / pharmacology*
  • Diclofenac / pharmacology
  • Humans
  • Ibuprofen / pharmacology
  • Isoprostanes / blood
  • Isoxazoles / pharmacology
  • Lactones / pharmacology*
  • Meloxicam
  • Naproxen / pharmacology
  • Oxidation-Reduction
  • Pyrazoles / pharmacology*
  • Sulfonamides / pharmacology*
  • Sulfones / pharmacology*
  • Thiazines / pharmacology
  • Thiazoles / pharmacology


  • Antioxidants
  • Cholesterol, LDL
  • Chromans
  • Cyclooxygenase Inhibitors
  • Isoprostanes
  • Isoxazoles
  • Lactones
  • Pyrazoles
  • Sulfonamides
  • Sulfones
  • Thiazines
  • Thiazoles
  • rofecoxib
  • Diclofenac
  • valdecoxib
  • Naproxen
  • Celecoxib
  • 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid
  • Meloxicam
  • Ibuprofen