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

dominates in the acute release of AA, the inducible
sPLA 2
contributes under conditions of sustained or
intense stimulation of AA production. Once liberated,
a portion of the AA is metabolized rapidly to oxygenated
products by several distinct enzyme systems,
including cyclooxygenases (COXs), lipoxygenases
(LOXs), and CYPs.
Products of Prostaglandin G/H Synthases. Synthesis of the PGs, PGI 2
,
and thromboxane, collectively termed prostanoids, is accomplished
in a stepwise manner by a complex of microsomal enzymes.
Successive metabolism of AA by the COX and hydroperoxidase
(HOX) activities of the PG endoperoxide G/H synthases, generate
the cyclic endoperoxide PGs G and H (Figure 33–1). Isomerases and
synthases affect the transformation of prostaglandin H 2
(PGH 2
) into
terminal prostanoids distinguished by substitutions on their
cyclopentane rings.
PGs of the E and D series are hydroxyketones, whereas the F α
PGs are 1,3-diols (Figure 33–1). A, B, and C PGs are unsaturated
ketones that arise nonenzymatically from PGE during extraction procedures;
it is unlikely that they occur biologically. Prostaglandin J 2
(PGJ 2
) and related compounds result from the dehydration of
prostaglandin D 2
(PGD 2
). Prostaglandin I 2
(PGI 2
, prostacyclin) has
a double-ring structure; in addition to a cyclopentane ring, a second
ring is formed by an oxygen bridge between carbons 6 and 9.
Thromboxanes (TXs) contain a six-member oxirane ring, instead of
the cyclopentane ring of the PGs. Levuglandins are formed by nonenzymatic
rearrangement of PGH 2
. These γ-ketoaldehydes are highly
reactive so that they are detected in vivo as their protein adducts
(Salomon et al., 1997). The main classes are further subdivided in
accord with the number of double bonds in their side chains, as indicated
by numerical subscripts. Dihomo-γ-linolenic acid is the precursor
of the one series, AA for the two series, and EPA for the three
series. Prostanoids derived from AA carry the subscript 2 and are
the major series in mammals. There is little evidence that one- or
three-series prostanoids are made in adequate amounts to be important
under normal circumstances. However, the health benefits of
dietary supplementation with ω-3 fatty acids, like EPA or the 22-
carbon-containing docosahexaenoic acid (DHA), remain a focus of
investigation.
The first enzyme in the prostanoid synthetic pathway is PG
endoperoxide G/H synthase, which is colloquially called
cyclooxygenase, or COX. There are two distinct COX isoforms,
COX-1 and COX-2 (Smith et al., 2000). COX-1, expressed constitutively
in most cells, is considered the dominant, but not exclusive,
source of prostanoids for housekeeping functions, such as cytoprotection
of the gastric epithelium (see Chapter 45). COX-2, in contrast, is
upregulated by cytokines, shear stress, and growth factors and is the
principle source of prostanoid formation in inflammation and cancer.
However, this distinction is overly simplistic; both enzymes contribute
to the generation of autoregulatory and homeostatic
prostanoids, and both can contribute to prostanoid formation during
inflammation. Indeed, there are physiological and pathophysiological
processes in which each enzyme is uniquely involved and others
in which they function coordinately (Smith and Langenbach, 2001).
In addition to 61% amino acid identity, the crystal structures
of COX-1 and COX-2 are remarkably similar (FitzGerald and Loll,
2001). Both isoforms are expressed as dimers homotypically inserted
into the endoplasmic reticular membrane; their COX activity oxygenates
and cyclizes unesterified AA to form prostaglandin G 2
(PGG 2
), whereas their HOX activity converts PGG 2
to PGH 2
(Smith
and Langenbach, 2001). These chemically unstable intermediates
are transformed enzymatically into the prostanoids by isomerases
and synthases. These enzymes are expressed in a relatively cellspecific
fashion such that most cells make one or two dominant
prostanoids. For example, COX-1-derived TxA 2
is the dominant
product in platelets, whereas COX-2-derived PGE 2
and TxA 2
dominate
in activated macrophages. Two classes of PGE synthases have
been cloned. Microsomal (m) PGE synthases 1 and 2 co-localize
with COX-2 in some, but not all, tissues and may be induced by
cytokines and tumor promoters. Similarly, cytosolic PGE synthase
often co-localizes with COX-1 and may be important in constitutive
formation of PGE 2
. Two forms of PGD synthase and PGF synthase
have been identified. In heterologous expression systems, COX-1
couples preferentially with TxA 2
and PGF synthase, whereas COX-2
prefers PGI 2
synthase (Smyth and FitzGerald, 2009).
Prostanoids are released from cells predominantly by facilitated
transport through the PG transporter and possibly other transporters
(Schuster, 2002).
Products of Lipoxygenases. LOXs are a family of non-heme
iron–containing enzymes that catalyze the oxygenation of polyenic
fatty acids to corresponding lipid hydroperoxides (Brash, 1999).
The enzymes require a fatty acid substrate with two cis double
bonds separated by a methylene group. AA, which contains several
double bonds in this configuration, is metabolized to hydroperoxy
eicosatetraenoic acids (HPETEs), which vary in the site of insertion
of the hydroperoxy group. Analogous to PGG 2
and PGH 2
, these
unstable intermediates, normally with S chirality, are further metabolized
by a variety of enzymes. HPETEs are converted to their corresponding
hydroxy fatty acid (HETE) either non-enzymatically or
by a peroxidase.
There are five active human LOXs—5(S)-LOX, 12(S)-LOX,
12(R)-LOX, 15(S)-LOX-1, and 15(S)-LOX-2—classified according
to the site of hydroperoxy group insertion. Human LOX products
are of the S stereoconfiguration with the exception of 12(R)-LOX.
Their expression is frequently cell specific (Brash, 1999); platelets
have only 12(S)-LOX, whereas leukocytes contain both 5(S)- and
12(S)-LOX (Figure 33–2). 12(R)-LOX is restricted in expression
mostly to the skin. The epidermal LOXs, which constitute a distinct
LOX subgroup, also include 15-LOX-2 and eLOX-3, the most
recently identified family member. eLOX-3 has been reported to
metabolize further 12(R)-HETE, the product of 12(R)-LOX, to a specific
epoxyalcohol product.
The 5-LOX pathway leads to the synthesis of the LTs, which
play a major role in the development and persistence of the inflammatory
response (Peters-Golden and Henderson, 2007) (Figure 33–2). A
nomenclature (e.g., LTB 4
, LTB 5
) similar to that of prostanoids applies
to the subclassification of the LTs. When eosinophils, mast cells, polymorphonuclear
leukocytes, or monocytes are activated, 5-LOX
translocates to the nuclear membrane and associates with 5-LOXactivating
protein (FLAP), an integral membrane protein that
facilitates AA to 5-LOX interaction (Evans et al., 2008). Drugs that
inhibit FLAP block LT production. A two-step reaction is catalyzed by
5-LOX: oxygenation of AA at C5 to form 5-HPETE, followed by
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CHAPTER 33
LIPID-DERIVED AUTACOIDS: EICOSANOIDS AND PLATELET-ACTIVATING FACTOR