CLINICAL CASES
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Conversion of arachidonate to PGH2 is a key regulatory step in
prostanoid biosynthesis. Each PGHS isoform catalyzes two separate reac-
tions (Figure 32-2). The first reaction (arachidonate^PGG2) involves inser-
tion of two molecules of oxygen and cyclization of the fatty acid backbone.
This step is catalyzed by the cyclooxygenase activity of PGHS-1 or -2; it is
these cyclooxygenase activities (also called COX-1 and COX-2) that are
inhibited by nonsteroidal antiinflammatory drugs (NSAIDs). The second
step (PGG2^PGH2) involves the reduction of the hydroperoxide on C15 to
an alcohol and is catalyzed by the peroxidase activity of PGHS-1 or -2.
Although both PGHS isoforms have cyclooxygenase and peroxidase activ-
ities and are structurally similar proteins, they have very distinct pathophysio-
logic functions. Many cells, including platelets and gastric mucosal cells, have
moderate levels of the “basal” isoform, PGHS-1. Functions attributed to
PGHS-1 include regulating hemostasis and vascular tone, renal function, and
maintaining gastric mucosal integrity. A smaller number of cells, such as
macrophages, vascular endothelial cells, and fibroblasts, dramatically upregu-
late levels of the “inducible” isoform, PGHS-2, in response to cytokines or
mitogens. PGHS-2 has been implicated in cell proliferation, inflammation,
carcinogenesis, and parturition.
Many cyclooxygenase inhibitors have been developed and their structures
are quite varied (Figure 32-3). All known inhibitors compete with fatty-acid
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