section 18.9
Metabolism of Eicosanoids
395
pga2
Iso m e r a se
PGC2
Iso m e r a se
COOH
FIGURE 18-23
Conversion of PGE
2
to PGA
2
, PGC
2
, and PGB
2
.
However, PGE
2
formation is favored by glutathione.
In the initial catabolic reaction of both compounds by
15-hydroxy-PG-dehydrogenase (15-PGDH), the reduced
NAD(P) formed in that reaction inhibits the first step.
Thus, the ratio of reduced to oxidized NAD(P) may control
the interconversion of PGE
2
and PGF2„ and also the first
step in their catabolism. This finding is important because
in many tissues PGE and PGF have opposing effects. PG
biosynthesis can also be regulated by activation of latent
forms of cyclooxygenase, promoted by catecholamines
and serotonin. The PGs synthesized differ from tissue to
tissue; within the same tissue, different cells may yield
products with antagonistic actions. For example, the lung
parenchymal cells may produce TXA2, while the lung vas-
cular endothelial cells may produce PGI
2
.
Catabolism of prostanoids occurs throughout the body,
but the lungs can remove most of the plasma PGs during
a single circulatory cycle. Despite this rapid removal, the
PGs have adequate access to target organs. Catabolism
starts with the reactions of 15-PGDH (oxidation of ally lie
-OH group at C
1 5
) and of PG reductase (reduction of the
A
13
double bond). 15-PGDH is found in the cytoplasm
(lungs), requires NAD+, and is specific for the
C
1 5
CS)
al-
cohol group. These reactions are followed by /1-oxidation,
oj-oxidation of the alkyl side chains, and elimination of the
products. The catabolism of PGE
2
and
PGP
2
U
is shown
in Figure 18-24. The
thromboxanes
(TX), first isolated
from human and equine thrombocytes (platelets), contain
an oxane ring. TXA
2
is synthesized from PGH
2
by mi-
crosomal thromboxane synthase. Thromboxane synthase
is inhibited by imidazole derivatives. TXA
2
has a very
short half-life (С
/ 2
= 30 seconds at 37°C and pH 7.5) and
undergoes rapid, nonenzymatic hydrolysis to the inactive
TXB
2
(Figure 18-22).
Prostacyclin
(PGI
2
) is an active and unstable metabolite
(t
\/2
= 3 minutes at 37°C and pH 7.5) formed from PGH
2
by prostacyclin synthase. PGI
2
has a double-ring structure
and is converted by nonenzymatic hydrolysis to
6
-keto-
PGF]a (Figure 18-22).
Biological Properties of Prostanoids
Many effects of prostanoids are mediated through adeny-
late cyclase or mobilization of Ca2+ from intracellular
stores. PGs increase cAMP in adenohypophysis, corpus
luteum, fetal bone, lung platelets, and thyroid but decrease
it in adipose tissue. Thromboxanes block the production
of cAMP by PGs and mobilize intracellular Ca2+. Thus,
many endocrine glands (e.g., adrenal cortex, ovary, pan-
creatic islets, parathyroids) secrete hormones in response
to PGs. Some of these effects are stimulation of steroid
hormone production in the adrenal cortex, insulin release,
thyroid hormone production, and progesterone secretion
from the corpus luteum.
In vitro
PGEs, notably PGEi,
inhibit adipocyte lipolysis—the basal rate as well as that
stimulated by catecholamine and other lipolytic hormones.
Fow doses of PGEi in humans tend to stimulate lipolysis
through stimulation of release of catecholamines. PGEs
stimulate the activity of osteoclasts with the mobiliza-
tion of Ca2+ from bone, an effect independent of that of
parathyroid hormone (Chapter 37).
Problems in delineating the primary actions of PGs arise
from their frequently opposing effects and from the dif-
ficulty of distinguishing between physiological and phar-
macological actions. In general, PGE
2
and PGF2o; have
opposing effects on smooth muscle tone, release of medi-
ators of immediate hypersensitivity, and cyclic nucleotide
