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

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SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
Hepoxilins
OH
CysLT
antagonists
e.g.: zafirlukast
pranlukast
montelukast
12 (S)–HETE
12 (R)–HETE
COOH
5 (S)–HETE
LTC 4
synthase
OH
12–LOXs
LTA 4
LTA 4
hydrolase
OH
OH
C LTC 5 H 11
LTB
S Cys Gly 4 4
Glu
γ–glutamyl transpeptidase
γ–glutamyl leukotrienase
OH
COOH
C LTD 5 H 11 S Cys Gly 4
dipeptidase
OH
COOH
C 5 H 11 S Cys
LTE 4 BLT 1
Arachidonic Acid
COOH
15–LOX–2
Acetylated COX–2
FLAP 5–LOX
COX–1 (after aspirin)
OOH
COX–2
15 (R)–HETE
COOH 5–LOX/COX
Inhibitors
5–LOX
e.g.: licofelone
(leukocytes)
5 (S)–HPETE Prostanoids
5–LOX
5–LOX–inhibitors
(see Figure 33–1)
O
e.g.: zileuton
COOH
15 (R)–epoxytetrane
COOH
COOH
12–LOX Epoxide
(platelets) hydrolases
12 (S)–HETE
12 (R)–HETE
CysLT 1 CysLT 2
BLT 2 ALX
15–epi–LXA 4
15–epi–LXB 4
HO OH
COOH
LXA 4
OH OH
COOH
HO OH LXB 4
COOH
15 (S)–HPETE
OOH
O
5–LOX
(neutrophils)
COOH
15 (S)–epoxytetrane
OH
Epoxide
hydrolases
Figure 33–2. Lipoxygenase pathways of arachidonic acid metabolism. 5-LOX-activating protein (FLAP) presents arachidonic acid to
5-LOX, leading to the generation of the LTs. CysLTs are shaded in gray. Lipoxins (shaded in orange) are products of cellular interaction
via a 5-LOX–12-LOX pathway or via a 15-LOX–5-LOX pathway. Biological effects are transduced via membrane-bound
receptors (blue boxes). The dashed line indicates putative ligand–receptor interactions. Zileuton inhibits 5-LOX but not the COX
pathways (expanded in Figure 33–1). Dual 5-LOX–COX inhibitors interfere with both pathways. CysLT antagonists prevent activation
of the CysLT1 receptor. See the text for abbreviations.
dehydration of 5-HPETE to an unstable 5,6-epoxide known as LTA 4
.
LTA 4
is transformed into bioactive eicosanoids by multiple pathways
depending on the cellular context: transformation by LTA 4
hydrolase
to a 5,12-dihydroxyeicosatetraenoic acid known as LTB 4
; conjugation
with GSH by LTC 4
synthase, in eosinophils, monocytes, and mast
cells, to form LTC 4
; and extracellular metabolism of the peptide moiety
of LTC 4
, leading to the removal of glutamic acid and subsequent
cleavage of glycine, to generate LTD 4
and LTE 4
, respectively (Peters-
Golden and Henderson, 2007). LTC 4
, LTD 4
, and LTE 4
, the cysteinyl
leukotrienes (CysLTs), were known originally as the slow-reacting
substance of anaphylaxis (SRS-A), first described >60 years ago.
LTB 4
and LTC 4
are actively transported out of the cell.
At least two isoforms of 15-LOX exists, 15-LOX-1 and 15-
LOX-2. The former prefers linoleic acid as a substrate and forms
15(S)-hydroxyoctadecadienoic acid, whereas the latter uses AA to
generate 15(S)-HETE. Platelet-type 12(S)-LOX generates 12(S)-
HETE from AA, whereas the leukocyte isozyme can synthesize both
12- and 15-HETE and often is referred to as 12/15-LOX. 12(S)-LOX
can further metabolize LTA 4
, the primary product of the 5-LOX pathway,
to form the lipoxins LXA 4
and LXB 4
. These mediators also can
arise through 5-LOX metabolism of 15-HETE. 15(R)-HETE, derived
from aspirin-acetylated COX-2, can be further transformed in leukocytes
by 5-LOX to the epilipoxins 15-epi-LXA 4
or 15-epi-LXB 4
, the
so-called aspirin-triggered lipoxins (Brink et al., 2003). 12-HETE
also can undergo a catalyzed molecular rearrangement to epoxyhydroxyeicosatrienoic
acids called hepoxilins. Two additional groups
of lipid mediators, the resolvins and protectins, may be generated
from EPA and DHA, through the sequential action of aspirin-acetylated
COX-2 and 5- or 15-LOX (Serhan et al., 2008).
The epidermal LOXs [12(R)-LOX, 15-LOX-2, and eLOX-3]
are distinct from “conventional” enzymes in their substrate preferences
and products (Furstenberger et al., 2007). Although the roles