398
chapter 18
Lipids I: Fatty Acids and Eicosanoids
then to leukotriene A
4
(5,6-oxido-7,9-lrarc.v-1 1,14-c/.s-
eicosatetraenoic
acid).
Leukotriene
A
4
(LTA4)
is
transformed by LTA
4
hydrolase into 5,12-dihyroxy-
eicosatetraenoic acid (leukotriene B4, LTB4) or into a glu-
tathione adduct with the formation of a thioether linkage
at Cö, (leukotriene C4, LTC4) by leukotriene C
4
synthase
(also known as glutathione S-transferase). Leukotriene
D
4
(LTD4) and LTE
4
are synthesized in the extracellular
space from LTC4. A specific transmembrane transporter
exports LTC
4
to the extracellular space. In the extracel-
lular space, removal of the glutamyl residue from LTC
4
by y-glutamyltransferase yields LTD
4
and the removal of
the glycyl residue from LTD
4
by a variety of dipeptidases
results in the formation LTE
4
(Figure 18-25).
The three cysteinyl linked leukotrienes, namely LTC4,
LTD
4
and LTE
4
are known collectively as cysteinyl
leukotrienes. All three cysteinyl leukotrienes are potent
mediators
of inflammation
and cause
microvascular
permeability,
chemotaxis
(particularly
eosinophils),
mucus hypersecretion, and neuronal stimulation. The
potential role of LTC
4
as a neuromessenger or modulator
has been implicated in an infant with LTC
4
synthase
deficiency.
The clinical features include muscular hy-
potonia,
psychomotor
retardation,
failure
to
thrive,
microcephaly, and a fatal outcome. In lung tissue mast
cells, eosinophils and alveolar macrophages possess the
enzyme activities to synthesize cysteinyl leukotrienes and
cause, in addition to above mentioned biological actions,
bronchial smooth muscle constriction and proliferation.
Thus, cysteinyl leukotrienes are important mediators of
C O O N a
FIGURE 18-26
Structures of leukotriene receptor antagonists, (a) Zafirlukast and
(b) montelukast.
immune-mediated inflammatory reactions of anaphylaxis
and are constituents of substances originally called “slow
reacting substances of anaphylaxis” (SRS-A). They are
several times more potent than histamine in constricting
airways and promoting tissue edema formation. The
proinflammatory effect of LTE
4
is less than that of LTC
4
and LTD4; it is excreted in the urine and is used as a
marker of leukotriene production.
Antileukotriene agents, which can be used in treatment
of allergen and exercise-induced asthma and allergic rhini-
tis, inhibit 5-lipoxygenase or the binding of the activator
protein with 5-lipoxygenase or antagonists of leukotriene
receptors at the target cell (e.g., airway epithelial cell).
The traditional drugs used for treatment of asthma include
inhaled corticosteroids, /
6 2
' agonists’
theophyllines.
Leukotriene receptor antagonists are orally active and are
a new class of antiasthmatic therapeutic agents (Figure
18-26).
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