Page 337 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 18 The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds 323

SYNTHESIS OF EICOSANOIDS F in PGE and PGF) and (2) in the number of double bonds in the
side chains (indicated by the subscript, eg, PGE , PGE ). PGH is
2
1
2
Products of Prostaglandin Endoperoxide metabolized by prostacyclin, thromboxane, and PGF synthases
Synthases (Cyclooxygenases) (PGIS, TXAS, and PGFS) to PGI , TXA , and PGF , respec-
2
2
2α
tively. Two additional enzymes, 9,11-endoperoxide reductase
Two unique COX isozymes convert AA into prostaglandin endo- and 9-ketoreductase, provide for PGF synthesis from PGH
2
2α
peroxides. PGH synthase-1 (COX-1) is expressed constitutively and PGE , respectively. At least three PGE synthases have been
2
2
in most cells. In contrast, PGH synthase-2 (COX-2) is readily identified: microsomal (m) PGES-1, the more readily inducible
inducible, its expression levels being dependent on the stimu- mPGES-2, and cytosolic PGES. There are two distinct PGDS
lus. COX-2 is an immediate early-response gene product that isoforms, the lipocalin-type PGDS and the hematopoietic PGDS.
is markedly up-regulated by shear stress, growth factors, tumor Several products of the arachidonate series are of current clini-
promoters, and cytokines, consistent with the presence of multiple cal importance. Alprostadil (PGE ) may be used for its smooth
1
regulatory motifs in the promoter and 3′ untranslated regions of muscle relaxing effects to maintain the ductus arteriosus patent in
the COX-2 gene. Put simply, COX-1 generates prostanoids for some neonates awaiting cardiac surgery and in the treatment of
“housekeeping” functions, such as gastric epithelial cytoprotec- impotence. Misoprostol, a PGE derivative, is a cytoprotective
1
tion, whereas COX-2 is the major source of prostanoids in inflam- prostaglandin used in preventing peptic ulcer and in combination
mation and cancer. However, there are additional physiologic and with mifepristone (RU-486) for terminating early pregnancies.
pathophysiologic processes in which each enzyme is uniquely Dinoprostone (PGE ) and PGF are used in obstetrics to induce
2
2α
involved, and others in which they function coordinately. For labor. Latanoprost and several similar compounds are topically
example, endothelial COX-2 is the primary source of vascular active PGF derivatives used in ophthalmology to reduce intra-
2α
prostacyclin (PGI ), whereas renal COX-2-derived prostanoids ocular pressure in open-angle glaucoma or ocular hypertension.
2
are important for normal renal development and maintenance Prostacyclin (PGI ) is synthesized mainly by the vascular endo-
2
of function. Nonsteroidal anti-inflammatory drugs (NSAIDs; thelium and is a powerful vasodilator and inhibitor of platelet
see Chapter 36) exert their therapeutic effects through inhibition aggregation. Synthetic PGI (epoprostenol) and PGI analogs
2
2
of the COXs. Most older NSAIDs, like indomethacin, sulin- (iloprost, treprostinil) are used to treat pulmonary hypertension
dac, meclofenamate, and ibuprofen nonselectively inhibit both and portopulmonary hypertension. In contrast, thromboxane
COX-1 and COX-2, whereas the selective COX-2 inhibitors (TXA ) has undesirable properties (platelet aggregation, vaso-
2
follow the order celecoxib = diclofenac = meloxicam = etodolac < constriction). Therefore TXA -receptor antagonists and synthesis
2
valdecoxib << rofecoxib < lumiracoxib = etoricoxib for increasing inhibitors have been developed for cardiovascular indications,
COX-2 selectivity. Aspirin acetylates and inhibits both enzymes although these (except for aspirin) have yet to establish a place in
covalently and hence irreversibly. Low doses (< 100 mg/d) inhibit clinical usage, and, in a recent large clinical trial, TXA receptor
2
preferentially, but not exclusively, platelet COX-1 (thus reducing antagonism failed to show superiority over low-dose aspirin for
thromboxane production), whereas higher doses inhibit both sys- secondary stroke protection.
temic COX-1 and COX-2. Genetic variations in human COX-2 All the naturally occurring COX products undergo rapid
variants have been linked with increased coronary heart disease metabolism to inactive products either by hydration (for PGI
2
risk, increases in some cancers, and reduced pain perception. and TXA ) or by oxidation (of the 15-hydroxyl group to the cor-
2
Both COX-1 and COX-2 function as homodimers inserted responding ketone) by prostaglandin 15-hydroxy prostaglandin
into the membrane of the endoplasmic reticulum to promote dehydrogenase (15-PGDH) after cellular uptake via an organic
the uptake of two molecules of oxygen by cyclization of AA to anion transporter polypeptide (OATP 2A1). Further metabolism
13
yield a C –C endoperoxide C hydroperoxide (Figure 18–2). is by Δ reduction, β-oxidation, and ω-oxidation. The inactive
11
9
15
This product is PGG , which is then rapidly modified by the per- metabolites are chemically stable and can be quantified in blood
2
oxidase moiety of the COX enzyme to add a 15-hydroxyl group and urine by immunoassay or mass spectrometry as a measure of
that is essential for biologic activity. This product is PGH . Both the in vivo synthesis of their parent compounds.
2
endoperoxides are highly unstable. Analogous families—PGH
1
and PGH and their subsequent 1-series and 3-series products—
3
are derived from homo-γ-linolenic acid and eicosapentaenoic Products of Lipoxygenase
acid, respectively. In both COX-1 and COX-2 homodimers, one The metabolism of AA by the 5-, 12-, and 15-lipoxygenases
protomer acts as the catalytic unit binding AA for oxygenation, (LOX) results in production of hydroperoxyeicosatetraenoic
while the other acts as an allosteric modifier of catalytic activity. acids (HPETEs), which rapidly convert to hydroxy derivatives
The prostaglandins, thromboxane, and prostacyclin, collec- (HETEs). 5-LOX, the most actively investigated pathway, gives
tively termed the prostanoids, are generated from PGH through rise to the leukotrienes (Figure 18–3) and is present in leukocytes
2
the action of downstream isomerases and synthases. These ter- (neutrophils, basophils, eosinophils, and monocyte-macrophages)
minal enzymes are expressed in a relatively cell-specific fashion, and other inflammatory cells such as mast cells and dendritic
such that most cells make one or two dominant prostanoids. The cells. This pathway is of great interest because it is associated
prostaglandins differ from each other in two ways: (1) in the sub- with asthma, anaphylactic shock, and cardiovascular disease.
2+
stituents of the pentane ring (indicated by the last letter, eg, E and Stimulation of these cells elevates intracellular Ca and releases