Inhibition of constitutive and inducible cyclooxygenase activity in human platelets and mononuclear cells by NSAIDs and Cox 2 inhibitors.
A range of NSAIDs and reported Cox 2 selective compounds were tested in human freshly isolated platelets and LPS-stimulated mononuclear cells to determine their potency and selectivity as inhibitors of constitutive (presumably Cox 1) and inducible (presumably Cox 2) cyclooxygenase respectively. All compounds tested were either equipotent at inhibiting constitutive and inducible cyclooxygenase or were selective for the inducible form. The most selective compound was Dup697 and the least selective, ketoprofen. Several compounds only produced a partial inhibition of constitutive cyclooxygenase as the maximum inhibitor concentration achievable in the assay was limited to 1 mM. With the exception of paracetamol, all compounds were able to produce full inhibition curves against the inducible form. Potency estimates against constitutive Cox compare closely with published data but most compounds were consistently more potent against the inducible isoform than in published data for human cloned, microsomal Cox 2. These data suggest that human mononuclear cells are either exquisitely sensitive to some NSAIDs or they may contain another Cox isoform as yet indistinguishable from Cox 2.
Grossman
C J
CJ
Molecular Science Department, Glaxo Research and Development, Ware, Hertfordshire, UK.
Wiseman
J
J
Lucas
F S
FS
Trevethick
M A
MA
Birch
P J
PJ
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D007660:Ketoprofen / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D013876:Thiophenes; C064874:DuP 697; D007660:Ketoprofen