substrate for binding to the cyclooxygenase site on the enzyme. Aspirin was one
of the earliest NSAIDs discovered and is now widely used as an analgesic and
antiinflammatory agent. More recently, aspirin has emerged as a very useful
antithrombotic agent because of its action against platelet cyclooxygenase
activity. Aspirin shows both archetypal modes of cyclooxygenase inhibition.
The first mode involves rapid reversible binding of inhibitor (I) at the cyclooxy-
genase site of the enzyme (E) to form an EI complex; the second mode involves
a slower conversion of EI to a higher affinity complex, EI' (Equation 1).
E + I o EI ^ EI'
EI and EI' cannot bind fatty acid and thus neither can catalyze the cyclooxy-
genase reaction. For aspirin, conversion of EI to EI' is accompanied by cova-
lent modification of the protein, making the transition irreversible.
Formation of the EI' complex produces a more powerful cyclooxygenase inhi-
bition because the inhibitor is not readily displaced by substrate and because
inhibition persists even when free inhibitor is removed. Flurbiprofen and
indomethacin are able to form EI' complexes with both PGHS-1 and -2,
although they do not covalently modify either protein. Ibuprofen forms only EI
complexes with both PGHS isoforms. The recently developed coxibs (such as
celecoxib and rofecoxib) derive their exquisitely selective inhibition of PGHS-2
cyclooxygenase from their ability to form noncovalent EI' complexes with
PGHS-2 and not with PGHS-1. This selectivity has made the coxibs very use-
ful for antiinflammatory and antiproliferative therapy with reduced gastroin-
testinal side effects, but it also makes them ineffective as antiplatelet agents and
consequently can increase cardiovascular risks.
C O M P R E H E N SIO N Q U E ST IO N S
[32.1] The coxibs, including celecoxib (Celebrex), are a recently developed
class of nonsteroidal antiinflammatory drugs (NSAIDs). The coxibs
show antiinflammatory actions without affecting platelet function.
These effects of the coxibs are best attributed to selective inhibition of
which of the following?
A. The cytosolic isozyme of phospholipase A2 (cPLA2)
B. The cyclooxygenase activity of the “basal” prostaglandin H syn-
thase isozyme (PGHS-1)
C. The cyclooxygenase activity of the “inducible” prostaglandin H
synthase isoform (PGHS-2)
D. The microsomal isozyme of prostaglandin E synthase (mPGES-1)
E. Prostacyclin (PGI2) synthase (PGIS)