PMID- 15530895
OWN - NLM
STAT- MEDLINE
DCOM- 20050415
LR  - 20181201
IS  - 0021-9150 (Print)
IS  - 0021-9150 (Linking)
VI  - 177
IP  - 2
DP  - 2004 Dec
TI  - Sulfone COX-2 inhibitors increase susceptibility of human LDL and plasma to 
      oxidative modification: comparison to sulfonamide COX-2 inhibitors and NSAIDs.
PG  - 235-43
AB  - 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.
FAU - Walter, Mary F
AU  - Walter MF
AD  - Elucida Research LLC, 100 Cummings Center, Suite 135L, Beverly, MA 01915, USA.
FAU - Jacob, Robert F
AU  - Jacob RF
FAU - Day, Charles A
AU  - Day CA
FAU - Dahlborg, Rachel
AU  - Dahlborg R
FAU - Weng, Yujia
AU  - Weng Y
FAU - Mason, R Preston
AU  - Mason RP
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - Ireland
TA  - Atherosclerosis
JT  - Atherosclerosis
JID - 0242543
RN  - 0 (Antioxidants)
RN  - 0 (Cholesterol, LDL)
RN  - 0 (Chromans)
RN  - 0 (Cyclooxygenase Inhibitors)
RN  - 0 (Isoprostanes)
RN  - 0 (Isoxazoles)
RN  - 0 (Lactones)
RN  - 0 (Pyrazoles)
RN  - 0 (Sulfonamides)
RN  - 0 (Sulfones)
RN  - 0 (Thiazines)
RN  - 0 (Thiazoles)
RN  - 0QTW8Z7MCR (rofecoxib)
RN  - 144O8QL0L1 (Diclofenac)
RN  - 2919279Q3W (valdecoxib)
RN  - 57Y76R9ATQ (Naproxen)
RN  - JCX84Q7J1L (Celecoxib)
RN  - S18UL9710X (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid)
RN  - VG2QF83CGL (Meloxicam)
RN  - WK2XYI10QM (Ibuprofen)
SB  - IM
MH  - Animals
MH  - Antioxidants/pharmacology
MH  - Celecoxib
MH  - Cholesterol, LDL/*metabolism
MH  - Chromans/pharmacology
MH  - Cyclooxygenase Inhibitors/*pharmacology
MH  - Diclofenac/pharmacology
MH  - Humans
MH  - Ibuprofen/pharmacology
MH  - Isoprostanes/blood
MH  - Isoxazoles/pharmacology
MH  - Lactones/*pharmacology
MH  - Meloxicam
MH  - Naproxen/pharmacology
MH  - Oxidation-Reduction
MH  - Pyrazoles/*pharmacology
MH  - Sulfonamides/*pharmacology
MH  - Sulfones/*pharmacology
MH  - Thiazines/pharmacology
MH  - Thiazoles/pharmacology
EDAT- 2004/11/09 09:00
MHDA- 2005/04/16 09:00
CRDT- 2004/11/09 09:00
PHST- 2004/11/09 09:00 [pubmed]
PHST- 2005/04/16 09:00 [medline]
PHST- 2004/11/09 09:00 [entrez]
AID - S0021-9150(04)00499-X [pii]
AID - 10.1016/j.atherosclerosis.2004.10.001 [doi]
PST - ppublish
SO  - Atherosclerosis. 2004 Dec;177(2):235-43. doi: 
      10.1016/j.atherosclerosis.2004.10.001.