DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Lipid-Derived Autacoids:
Eicosanoids and Platelet-
Activating Factor
Emer M. Smyth, Tilo Grosser,
and Garret A. FitzGerald
Membrane lipids supply the substrate for the synthesis
of eicosanoids and platelet-activating factor (PAF).
Eicosanoids—arachidonate metabolites, including
prostaglandins (PGs), prostacyclin (PGI 2
), thromboxane
A 2
(TxA 2
), leukotrienes (LTs), lipoxins, and
hepoxilins—are not stored but are produced, by most
cells, when a variety of physical, chemical, and hormonal
stimuli activate acyl hydrolases that make arachidonate
available. Membrane glycerophosphocholine
derivatives can be modified enzymatically to produce
PAF. PAF is formed by a smaller number of cell types,
principally leukocytes, platelets, and endothelial cells.
Eicosanoids and PAF lipids contribute to inflammation,
smooth muscle tone, hemostasis, thrombosis, parturition,
and gastrointestinal secretion. Several classes of
drugs, most notably aspirin, the traditional non-steroidal
anti-inflammatory agents (tNSAIDs), and the specific
inhibitors of cyclooxygenase-2 (COX-2), such as the
coxibs, owe their principal therapeutic effects to blockade
of eicosanoid formation. To understand the therapeutic
potential of selective inhibitors of eicosanoid
synthesis and action, we must first review the synthesis,
metabolism, and mechanism of action of eicosanoids
and PAF.
EICOSANOIDS
History. In 1930, Kurzrok and Lieb, two American gynecologists,
observed that strips of uterine myometrium relax or contract when
exposed to semen. Subsequently, Goldblatt in England and von
Euler in Sweden reported independently on smooth muscle-contracting
and vasodepressor activities in seminal fluid and accessory reproductive
glands. In 1935, von Euler identified the active material as
a lipid-soluble acid, which he named prostaglandin, inferring its origin
in the prostatic gland. Samuelsson, Bergström, and their colleagues
elucidated the structures of prostaglandin E 1
(PGE 1
) and
prostaglandin F 1
α (PGF 1
α) in 1962. In 1964, Bergström and
coworkers, and van Dorp and associates, independently achieved
biosynthesis of PGE 2
from arachidonic acid (AA). Discovery of
TxA 2
, PGI 2
, and the LTs followed. Vane, Smith, and Willis reported
that aspirin and NSAIDs act by inhibiting prostaglandin biosynthesis
(Vane, 1971). This remarkable period of discovery linked the
Nobel Prize of von Euler in 1970 to that of Bergström, Samuelsson,
and Vane in 1982.
PGs, LTs, and related compounds are called eicosanoids, from
the Greek eikosi (“twenty”). Precursor essential fatty acids contain 20
carbons and three, four, or five double bonds: 8,11,14-eicosatrienoic
acid (dihomo-γ-linolenic acid), 5,8,11,14-eicosatetraenoic acid [AA;
Figure 33–1], and 5,8,11,14,17-eicosapentaenoic acid (EPA). In
humans, AA, the most abundant precursor, is either derived from
dietary linoleic acid (9,12-octadecadienoic acid) or ingested directly
as a dietary constituent. EPA is a major constituent of oils from fatty
fish such as salmon.
Biosynthesis. Biosynthesis of eicosanoids is limited by
the availability of substrate and depends primarily on
the release of AA, esterified in the sn-2 domain of cell
membrane phospholipids, or other complex lipids, to
the eicosanoid-synthesizing enzymes by acyl hydrolases,
most notably phospholipase A 2
(PLA 2
). Chemical
and physical stimuli activate the Ca 2+ -dependent
translocation of group IV A
cytosolic PLA 2
(cPLA 2
),
which has a high affinity for AA, to the membrane,
where it hydrolyzes the sn-2 ester bond of membrane
phospholipids (particularly phosphatidylcholine and
phosphatidylethanolamine), releasing arachidonate.
Multiple additional PLA 2
isoforms (secretory [s] and
Ca 2+ -independent [i] forms) have been characterized.
Under nonstimulated conditions, AA liberated by
iPLA 2
is reincorporated into cell membranes, so there
is negligible eicosanoid biosynthesis. Although cPLA 2