Page 338 - Basic _ Clinical Pharmacology ( PDFDrive )

324 SECTION IV Drugs with Important Actions on Smooth Muscle

COOH

Arachidonic acid

Cyclooxygenase COX-1
COX-2

O COOH
O
PGG 2
OOH

Peroxidase COX-1
COX-2
O
COOH COOH
O
O
COOH OH PGH 2 PGI 2
O (prostacyclin)
O
TXA
OH 2
(thromboxane) OH
PGF HO OH
O COOH
COOH
HO O
OH PGD 2
HO OH PGE 2 COOH

HO OH PGF 2α COOH

O 15-deoxy- 12,14
-PGJ 2

FIGURE 18–2 Prostanoid biosynthesis. Compound names are enclosed in boxes.

arachidonate; incorporation of molecular oxygen by 5-LOX, inhibitors, cysteinyl leukotriene-receptor antagonists, inhibitors
in association with 5-LOX-activating protein (FLAP), yields of FLAP, and phospholipase A inhibitors. Variants in the human
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5(S)-HPETE, which is then further converted by 5-LOX to 5-LOX gene (ALOX5) or the cysteinyl receptors (CYSLTR1
the unstable epoxide leukotriene A (LTA ). This intermediate or CYSLTR2) have been linked with asthma and with altered
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is either converted to the dihydroxy leukotriene B (LTB ), via response to antileukotriene drugs.
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the action of LTA hydrolase, or is conjugated with glutathione LTA , the primary product of 5-LOX, can also be converted
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to yield leukotriene C (LTC ), by LTC synthase. Sequential with appropriate stimulation via 12-LOX in platelets in
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degradation of the glutathione moiety by peptidases yields LTD vitro to the lipoxins LXA and LXB . These mediators can
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and LTE . These three products, LTC , D , and E , are called also be generated through 5-LOX metabolism of 15(S)-
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cysteinyl leukotrienes. Although leukotrienes are predominantly HETE, the product of 15-LOX-2 metabolism of arachi-
generated in leukocytes, nonleukocyte cells (eg, endothelial cells) donic acid. The stereochemical isomer, 15(R)-HETE, may
that express enzymes downstream of 5-LOX/FLAP can take up be derived from the action of aspirin-acetylated COX-2 and
and convert leukocyte-derived LTA in a process termed transcel- further transformed in leukocytes by 5-LOX to 15-epi-LXA
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lular biosynthesis. Transcellular formation of prostaglandins has or 15-epi-LXB , the so-called aspirin-triggered lipoxins. The
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also been shown; for example, endothelial cells can use platelet 15-LOX-1 isoform prefers linoleic acid as a substrate, forming
PGH to form PGI . 13(S)-hydroxyoctadecadienoic acid, while the sequential action
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LTC and LTD are potent bronchoconstrictors and are of 15-LOX-1 and 5-LOX can convert the omega-3 fatty acid
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secreted in asthma and anaphylaxis. There are four current docosahexaenoic acid (DHA) to the resolvins, potentially anti-
approaches to antileukotriene drug development: 5-LOX enzyme inflammatory, pro-resolving lipids. Synthetic resolvins, lipoxins,