chapter 18
Lipids I: Fatty Acids and Eicosanoids
FIGURE 18-20
Ring structures of prostaglandins (PG), prostacyclin (PGI), and thromboxane (TXs). Groups that lie behind the plane of
the ring are shown by || || and those that lie above the plane by <
synthase, which is a cyclooxygenase and a peroxidase. Cy-
clooxygenase activity (the rate-limiting reaction) results
in 15-hydroperoxy-9,11-endoperoxide (PGG
), which is
converted to a 9,11-endoperoxide (PGH2) by the per-
oxidase activity. There are two isoforms of cyclooxy-
genase (COX), which have been designated as COX1
and COX2. Both forms are membrane-associated en-
zymes. COX1 is constitutively expressed in many tissues,
where arachidonic acid metabolites play a role in pro-
tective “housekeeping” homeostatic functions. Some of
the COX1 mediated normal physiological functions in-
clude gastric cytoprotection and limiting acid secretion
(Chapter 12), maintenance of renal blood flow, vascu-
lar homeostasis, and hemostasis (e.g., antiplatelet effects,
Chapter 36). COX2 activity, on the other hand, is normally
undetectable in most tissues and it is principally an in-
ducible enzyme. In cells such as monocytes, macrophages,
synoviocytes, endothelial cells, and chondrocytes, COX2
is expressed at high levels after induction by inflammatory
mediators (e.g., interleukin
- 1
and tumor necrosis factor)
and growth factors. COX2 enzymatic activity initiates the
synthesis of arachidonic acid metabolites that mediate
pain, inflammation, cellular differentiation and mitogene-
sis. For example, PG
is chemotactic for neutrophils and
causes changes in vascular permeability facilitating
extravasation of leukocytes. Although COX2 is generally
an inducible enzyme, it is constitutively expressed in de-
veloping kidney and brain and, therefore, may be involved
in their normal development and proper maturation.
The two unique isoforms, COX1 and COX2, are struc-
turally similar but they are encoded by separate genes
differing in their tissue distribution and expression. The
COX1 gene contains a promoter region without a TATA
sequence and is constitutively expressed. In contrast, the
COX2 gene contains DNA segments that allow for rapid
up regulation in response to appropriate stimuli. The anti-
inflammatory action of glucocorticoids have no effect on
the regulation of the COX
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