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

938
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
O
O
11,12-EET
Isoprostanes
O 14,15-EET
O
8,9-EET
O
O
O
HO
COOH
5,6-EET
COOH
Free radical
attack
COOH
COOH
OH
OH
CYPs
LOXs
5-LOX/COX
Inhibitors
e.g.:
Licofelone
HETEs
Leukotrienes
Lipoxins
(See Figure 33-2)
TXA synthase
TxA 2
COOH
mPGE synthase
cPGE synthase
PGE 2
COOH
hydroperoxidase
cyclooxygenase
O
O
O
O
Arachidonic Acid
PGF
synthase
COX-1
COX-2
OH
HO
O
COOH
COOH
PGG
OOH
2
COX-1
COX-2
COOH
PGH 2
L-PGD
synthase
H-PGD
synthase
OH
Endocannabanoids:
Arachidonylethanolamide
2-arachidonoylglycerol
Aspirin
tNSAIDs
selective
COX-2 inhibitors
e.g.: coxibs
O
PGI synthase
PGI 2
OH
OH
COOH
PGD 2
cannabanoid
receptors
COX-2
Glyceryl
prostaglandins
acetylated
COX-2
Epi-lipoxins
(See Figure 33-2)
COOH
HO
COOH
COOH
HO
OH
PGF 2α O 15–deoxy–Δ 12,14 –PGJ 2
TP α, β EP 1 EP 2 EP 3A-D EP 4 FP DP DP 2
IP
Figure 33–1. Metabolism of arachidonic acid (AA). The cyclooxygenase (COX) pathway is highlighted in gray. The lipoxygenase (LOX)
pathways are expanded in Figure 33–2. Major degradation pathways are shown in Figure 33–3. Cyclic endoperoxides (PGG 2
and PGH 2
)
arise from the sequential cyclooxygenase and hydroperoxidase actions of COX-1 or COX-2 on AA released from membrane phospholipids.
Subsequent products are generated by tissue-specific synthases and transduce their effects via membrane-bound receptors (blue
boxes). Dashed lines indicate putative ligand–receptor interactions. Epoxyeicosatrienoic acids (EETs; shaded in blue) and isoprostanes
are generated via CYP activity and non-enzymatic free radical attack, respectively. COX-2 can use modified arachidonoylglycerol, an endocannabinoid,
to generate the glyceryl prostaglandins. Aspirin and tNSAIDs are nonselective inhibitors of COX-1 and COX-2 but do not
affect LOX activity. Epilipoxins are generated by COX-2 following its acetylation by aspirin (see Figure 33–2). Dual 5-LOX–COX
inhibitors interfere with both pathways. See the text for other abbreviations.