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

of epidermal LOXs in normal skin function are not clear, they may
be relevant for skin barrier function and adipocyte differentiation.
Epidermal accumulation of 12(R)-HETE is a feature of psoriasis and
ichthyosis. Inhibitors of 12(R)-LOX are under investigation for the
treatment of these proliferative skin disorders.
Products of CYPs. Multiple CYPs can metabolize AA (Capdevila and
Falck, 2002). The epoxyeicosatrienoic acids (EETs), formed by CYP
epoxygenases, primarily CYP2C and CYP2J in humans, have been
a primary focus of research. Four regioisomers (14,15-; 11,12-; 8,9-;
and 5,6-EETs), each containing a mixture of the (R,S) and (S,R)
enantiomers, are formed in a CYP isoform–specific manner. EETs
are synthesized in endothelial cells, where they function as endotheliumderived
hyperpolarizing factors (EDHFs), particularly in the coronary
circulation (Campbell and Falck, 2007). Their biosynthesis can
be altered by pharmacological, nutritional, and genetic factors that
affect CYP expression (see Chapter 6). CYP hydroxylases (primarily
CYPs 4A, 4F) generate hydroxyeicosatetraenoic acids (16-, 17-, 18-
, 19-, or 20-HETE), with 20-HETE being the principle product
CYP-derived AA metabolite in vascular smooth muscle cells. 20-
HETE is generated in response to smooth muscle cell stretch or to
vasoactive agents, including angiotensin II (AngII).
EETs are metabolized by numerous pathways. The corresponding
biologically less active (or inactive) dihydroxyeicosatrienoic
acids (DHETs) are formed by epoxide hydrolases (EHs), whereas
lysolipid acylation results in incorporation of EETs and DHETs into
cellular phospholipids, where they can be stored. Inhibitors of EHs
currently are under investigation. Glutathione conjugation and oxidation
by COX and CYPs generate a series of glutathione conjugates,
epoxyprostaglandins, diepoxides, tetrahydrofuran (THF) diols, and
epoxyalcohols, whose biological relevance is not known. Similarly,
20-HETE can be converted by the COX pathway to the 20-hydroxy
PGs. Intracellular fatty acid–binding proteins (FABPs) may bind
EETs and DHETs differentially, thus modulating their metabolism,
activities, and targeting.
Other Pathways. In addition to enzymatic formation of eicosanoids,
several families of eicosanoid isomers are generated at significant
concentrations in vivo by non-enzymatic free radical catalyzed oxidation
of AA. The best characterized of these isoeicosanoids are the
F 2
-isoprostanes (F 2
-IsoPs) (Lawson et al., 1999; Fam and Morrow,
2003; Milne et al., 2008). Unlike PGs, these compounds are initially
formed esterified in phospholipids, after which they are hydrolyzed
to their free form by phospholipases, including PAF acetylhydrolase
(Stafforini et al., 2006), which then circulate and are metabolized
and excreted into urine. Their production is not inhibited in vivo by
inhibitors of COX-1 or COX-2, but their formation is suppressed by
antioxidants. The PGF 2α
isomer, 8-iso-PGF 2α
, was the first F 2
-IsoP
to be identified. Measuring levels of these compounds in plasma and
urine is considered the most accurate method to assess oxidative
stress status in vivo, and increased levels are found in a large number
of clinical conditions. Isoprostanes correlate with cardiovascular
risk factors, but their use as predictors of coronary events remains an
area of active investigation. Of particular interest is the recent finding
that levels of F 2
-IsoPs predict 30-day outcome in acute coronary
syndrome (LeLeiko et al., 2009).
In addition to F 2
-IsoPs, other PG-like isomers, including
D 2
/E 2
-IsoPs, isothromboxanes, and isolevuglandins (alternatively
termed isoketals), are also formed in vivo by non-enzymatic oxidation
of AA (Brame et al., 2004). Isoleukotrienes are also generated nonenzymatically.
Because several isoprostanes can activate prostanoid
receptors, it has been speculated that they may contribute to the
pathophysiology of inflammatory responses in a manner insensitive
to COX inhibitors.
In the brain, the endocannabinoids arachidonylethanolamide
(anandamide) and 2-arachidonoylglycerol are endogenous ligands
of cannabinoid receptors (Bisogno, 2008). They mimic several pharmacological
effects of Δ9-tetrahydrocannabinol, the active principle
of Cannabis sativa preparations such as hashish and marijuana,
including inhibition of adenylyl cyclase, inhibition of L-type Ca 2+
channels, analgesia, and hypothermia. Several pathways have been
proposed, but the prevalent one for biosynthesis in vivo remains
unclarified. Conversion of anandamide and 2-arachidonylglycerol
by COX-2 generates PG-ethanolamides (prostamides) and PG-glyceryl
esters (Woodward et al., 2008); their biological significance remains
to be clarified.
Inhibitors of Eicosanoid Biosynthesis. A number of the
biosynthetic steps just described can be inhibited by
drugs. Inhibition of PLA 2
decreases the release of the
precursor fatty acid and thus the synthesis of all its
metabolites. Because PLA 2
is activated by Ca 2+ and
calmodulin, it may be inhibited by drugs that reduce
the availability of Ca 2+ . Glucocorticoids also inhibit
PLA 2
, but they appear to do so indirectly by inducing
the synthesis of a group of proteins termed annexins
(formerly lipocortins) that modulate PLA 2
activity (see
Chapter 42). Glucocorticoids also downregulate
induced expression of COX-2 but not of COX-1.
Aspirin and tNSAIDs originally were found to prevent
the synthesis of PGs from AA in tissue homogenates
(Vane, 1971). It is now known that these drugs inhibit
the COX, but not the POX, moieties of both PG G/H
synthases, and thus the formation of their downstream
prostanoid products. In addition, these drugs do not
inhibit LOXs and may cause increased formation of
LTs by shunting of substrate to the LOX pathway. LTs
may contribute to the GI side effects associated with
NSAIDs. Dual inhibitors of the COX and 5-LOX pathways,
in particular licofelone, are under investigation
(Kulkarni and Singh, 2007). However, the exact interplay
between these enzyme families remains to be
defined.
COX-1 and COX-2 differ in their sensitivity to
inhibition by certain anti-inflammatory drugs (Grosser
et al., 2006). This observation has led to the recent
development of selective inhibitors of COX-2, including
the coxibs (see Chapter 34). It was hypothesized
that these drugs would have therapeutic advantages
over tNSAIDs, many of which are non-selective for
COX-1/2. COX-2 is the predominant COX at sites of
inflammation, whereas COX-1 is the major source of
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CHAPTER 33
LIPID-DERIVED AUTACOIDS: EICOSANOIDS AND PLATELET-ACTIVATING FACTOR