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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

2

), 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

E

2

is chemotactic for neutrophils and

PGI

2

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

1

gene.