title: Sulfone COX-2 inhibitors increase susceptibility of human LDL and plasma to oxidative modification: comparison to sulfonamide COX-2 inhibitors and NSAIDs.
abstract: 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.
authors.affiliation: Elucida Research LLC, 100 Cummings Center, Suite 135L, Beverly, MA 01915, USA.
authors.forename: Mary F
authors.initials: MF
authors.lastname: Walter
authors.forename: Robert F
authors.initials: RF
authors.lastname: Jacob
authors.forename: Charles A
authors.initials: CA
authors.lastname: Day
authors.forename: Rachel
authors.initials: R
authors.lastname: Dahlborg
authors.forename: Yujia
authors.initials: Y
authors.lastname: Weng
authors.forename: R Preston
authors.initials: RP
authors.lastname: Mason
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D000068579:Celecoxib; D008078:Cholesterol, LDL / Q000378:metabolism*; D002839:Chromans / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004008:Diclofenac / Q000494:pharmacology; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology; D028421:Isoprostanes / Q000097:blood; D007555:Isoxazoles / Q000494:pharmacology; D007783:Lactones / Q000494:pharmacology*; D000077239:Meloxicam; D009288:Naproxen / Q000494:pharmacology; D010084:Oxidation-Reduction; D011720:Pyrazoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology*; D013843:Thiazines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D000975:Antioxidants; D000068579:Celecoxib; D008078:Cholesterol, LDL; D002839:Chromans; D016861:Cyclooxygenase Inhibitors; D004008:Diclofenac; D007052:Ibuprofen; D028421:Isoprostanes; D007555:Isoxazoles; D007783:Lactones; D000077239:Meloxicam; D009288:Naproxen; D011720:Pyrazoles; D013449:Sulfonamides; D013450:Sulfones; D013843:Thiazines; D013844:Thiazoles; C116926:rofecoxib; C406224:valdecoxib; D000096926:Benzenesulfonamides; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid