section 18.9
Metabolism of Eicosanoids
The amino acid sequence homology of COX1 and
COX2 is about 60%. However, in the region of the ac-
tive site the amino acid homology is about 90% and both
isoforms contain a long narrow largely hydrophobic chan-
nel with a hairpin bend at the end to accommodate the
substrate arachidonic acid. A unique single-amino-acid
difference in the wall of the hydrophobic channel (posi-
tion 523) of COX1 and COX2 has been used to develop
specific COX2 inhibitors. At position 523, COX1 has an
isoleucine residue whereas COX2 has a valine residue
which is smaller by a single CH
group. The presence
of the less bulky valine residue in the COX2 hydrophobic
channel provides access for COX2 selective inhibitors. In
COX1 the bulkier isoleucine residue prevents the entry of
COX2 selective inhibitors.
In the treatment and management of pain and inflam-
mation produced by arachidonic acid metabolites, COX
inhibitors are widely used. These agents arc known as
steroidal anti-inflammatory drugs
(NSAIDs). Acetylsal-
icylate (aspirin) is the classic anti-inflammatory and anal-
gesic drug. Aspirin is an irreversible inhibitor of both
COX1 and COX2 and it inhibits by acetylation of the hy-
droxyl group of the serine residue located at the active
site of the enzymes. There are nonaspirin NSAIDs, the
majority of which are organic acids (e.g., indomethacin,
ibuprofen), that are reversible inhibitors of both COX1 and
COX2. These inhibitors form a hydrogen bond with an
arginine residue at position 120 of both COX1 and COX2
in the channel and block the entry of arachidonic acid.
Because of their non-selectivity, aspirin and nonaspirin
NSAIDs cause undesirable side effects due to inhibition
of the “housekeeping” COX1 enzyme. The side effects
include gastrointestinal disorders, renal dysfunction and
bleeding tendency. Thus, a COX2 selective or preferential
inhibitor that spares COX1 activity is valuable in the treat-
ment of pain and inflammation. Based on the biochemical
differences between COX1 and COX2, drugs have been
designed with COX2 inhibitor activity, which are associ-
ated with a markedly lower incidence of gastrointestinal
injury. These drugs often possess sulfonyl, sulfone, or sul-
fonamide functional groups that bind with the COX2 side
pocket in the hydrophobic channel. Examples of COX2
inhibitors are celecoxib, which is a
,5-diarylpyrazole sul-
fonamide, and rofecoxib, which is a methylsulfonylphenyl
derivative (Figure 18-21). Since nitric oxide (NO) protects
gastric mucosa (Chapter 17), a NO moiety linked to con-
ventional NSAIDs may negate the gastric toxic effects due
to prostaglandin deficiency. Such drugs of NO-NSAIDs
are currently being tested.
Other potential uses for COX inhibitors (in particu-
lar for COX2 inhibitors) may include the treatment of
Alzheimer’s disease and colon cancer. In Alzheimer’s dis-
FIGURE 18-21
Structures of cyclooxygenase-2 (COX2) selective inhibitors. (A) Celecoxib
and (B) Rofecoxib.
ease it is thought that an inflammatory component may
lead to deposition of ^-amyloid protein in neuritic plaques
in the hippocampus and cortex (Chapter 4). The potential
use of COX2 inhibitors in colon cancer arises from studies
with experimental animals in which COX2 activity is re-
lated to the promotion and survival of intestinal adenomas
and colon tumors. The cyclooxygenase reaction is also
inhibited by arachidonic acid analogues such as
5 ,8 ,1 1 ,1 4 - E ic o s a te tr a y n o ic a c i d
is converted to PGD
, PGE2, PGF2o., prostacyclin
), and thromboxane A
(TXA2) by specific enzymes
(Figure 18-22). PGA
is obtained from PGE
by dehydra-
tion. Since PGC
and PGB
are isomers of PGA2, they
can be synthesized by isomerases. The formation of these
compounds is shown in Figure 18-23. In some tissues,
and PGF
undergo interconversion:
The NAD(P)+ inhibits the conversion of PGE
to PGF2„,
while reducing agents favor the formation of PGF2„.
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