Arachidonic acid

Cyclooxygenases

Lipoxygenases

P450-Monooxygenases

Prostaglandins Thromboxanes

HETEs, leukotrienes

Epoxy-eicosanoids Hydroxy-eicosanoids

Figure 1 Arachidonic acid metabolic pathways. (see color insert)

Table I Physiologic Activities of Products of Cyclooxygenase Activity.

PGE2 Vasodilatation, bronchodilatation, inhibition of gastric acid secretion, gastric mucosal protection, hyperalgesia, pyrexia, increased uterine contractility

PGD2 Vasodilatation, regulation of renal blood flow, pulmonary artery constriction, bronchoconstriction PGF2a Pulmonary artery constriction, bronchoconstriction, increased uterine contractility PGI2 Vasodilatation, inhibition of platelet aggregation

TxA2 Vasoconstriction, bronchoconstriction, promotion of platelet aggregation, increased membrane permeability, neutrophil activation generation, vasomotor tone, vascular permeability, febrile response, and uterine contractility. Stimulation of the cell by growth factors, cytokines, or mechanical trauma leads to mobilization of arachidonic acid from the phospholipid membrane, followed by cyclooxygenase-mediated conversion of arachidonic acid to a short-lived intermediate, prostaglandin H2 (PGH2). This molecule is then modified by specific enzymes to produce a variety of bioactive substances (Table I) that share a similar chemical structure (Figure 2). Cell-specific expression of arachidonic metabolites exists as a result of differential expression of both downstream metabolizing enzymes and receptor isoforms. For example, epithelial cells contain prostaglandin syn-thetase, leading to the production of prostaglandin E2 (PGE2), platelets contain thromboxane synthetase and therefore produce thromboxane A2 (TxA2), and endothelial cells produce prostaglandin I2 (PGI2), also known as prostacy-clin, through the activity of prostacyclin synthase. There are at least nine known prostaglandin receptor forms, conveying an additional level of tissue specificity to prostaglandin-mediated activities. Four of the receptor subtypes bind PGE2 (EP1-EP4), two bind PDG2 (DP1, DP2), and separate recep-

Cyclooxygenases

PGE,

PGH.

PGD.

TxA,

Figure 2 Tissue-specific products of cyclooxygenase activity. (see color insert)

tors bind PGF2o (FP), PGI2 (IP) and TxA2 (TP). These receptors are transmembrane G protein—coupled proteins linked to a number of different signaling pathways. In complex tissues, receptors for a wide variety of prostaglandins are present on the surface of various components, such as epithelial cells, stromal fibroblasts, stromal endothelial cells, and inflammatory cells.

Until 1991, only one form of cyclooxygenase was recognized. This family of enzymes is now known to contain at least two forms, each with distinct roles in tissue regulation (Table II). Cyclooxygenase-1 (Cox-1) is constitutively expressed in the gastrointestinal mucosa, kidneys, platelets, and vascular endothelium and is responsible for maintenance of normal physiologic function of these tissues. Cyclooxygenase-2 (Cox-2) was identified in the early 1990s as a distinct enzyme associated primarily with inflammation. Cox-2 is the product of an intermediate-early response gene whose tissue expression is increased 20-fold in response to growth factors, cytokines, and tumor promoters. Cox-2 is not found in significant quantities in the absence of stimulation, which explains why it remained undetected as a distinct molecule for 20 years.

The Lipoxygenase Pathway

Lipoxygenases convert arachidonic, linoleic, and other polyunsaturated fatty acids into biologically active hydroperoxy derivatives that modulate cell signaling. In mammals, lipoxygenases are classified according to their positional specificity for fatty acid oxygenation, and are therefore designated as 5-, 8-, 12-, or 15-lipoxygenase. The 12- and 15-lipoxygenases are further differentiated according to whether they are derived from platelets (12-S-LOX). epidermis (12-^-LOX and 15-LOX-2), or reticulocytes (12-LOX-1).

The physiologic effects of lipoxygenase metabolites have not been characterized as extensively as those produced by cyclooxygenase activity. The 5-, 8-, and 12-LOX isoforms result in production of hydroxyeicosatetraenoic acids (HETEs), including 5-S-HETE, LTB4, 8-S-HETE, and 12-HETE (Figure 3). In general, these metabolites increase cell proliferation, contribute to inflammatory changes, and

Table II Cyclooxygenases.

Constitutive expression

Inducible expression

Effects

Inhibited by

Cox-1 Gastric epithelium, platelets

Cox-2 Kidney, brain

Rare or none under physiological conditions

Induced in most tissues by growth factors, inflammatory cytokines, neurotransmitters, oxidative stress

Pain, platelet activation, protection of gastric mucosa

Pain, inflammation, fever, angiogenesis, tumorigenesis

Most NSAIDs, including aspirin; with minimal or no inhibition by Cox-2 selective agents

Most NSAIDs

Arachidonic Acid

S-LOX

5-LOX

Figure 3 Products of lipoxygenase metabolism. (see color insert)

extensively studied is the CYP4A subfamily. The CYP4A epoxygenase metabolizes arachidonic acid and linoleic acid to a set of compounds known as epoxyeicosatrienoic acids (EETs). The EETs are further metabolized by CYP4A to 19-and 20-hydroxylepoxyeicosatrienoic acids (HEETs). These mediators are vasodilators and modulators of intracellular Ca2+, Na+, and K+ transport.

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