Lipids I: Fatty Acids and Eicosanoids
then to leukotriene A
transformed by LTA
hydrolase into 5,12-dihyroxy-
eicosatetraenoic acid (leukotriene B4, LTB4) or into a glu-
tathione adduct with the formation of a thioether linkage
at Cö, (leukotriene C4, LTC4) by leukotriene C
(also known as glutathione S-transferase). Leukotriene
(LTD4) and LTE
are synthesized in the extracellular
space from LTC4. A specific transmembrane transporter
to the extracellular space. In the extracel-
lular space, removal of the glutamyl residue from LTC
by y-glutamyltransferase yields LTD
and the removal of
the glycyl residue from LTD
by a variety of dipeptidases
results in the formation LTE
The three cysteinyl linked leukotrienes, namely LTC4,
are known collectively as cysteinyl
leukotrienes. All three cysteinyl leukotrienes are potent
mucus hypersecretion, and neuronal stimulation. The
potential role of LTC
as a neuromessenger or modulator
has been implicated in an infant with LTC
The clinical features include muscular hy-
microcephaly, and a fatal outcome. In lung tissue mast
cells, eosinophils and alveolar macrophages possess the
enzyme activities to synthesize cysteinyl leukotrienes and
cause, in addition to above mentioned biological actions,
bronchial smooth muscle constriction and proliferation.
Thus, cysteinyl leukotrienes are important mediators of
C O O N a
Structures of leukotriene receptor antagonists, (a) Zafirlukast and
immune-mediated inflammatory reactions of anaphylaxis
and are constituents of substances originally called “slow
reacting substances of anaphylaxis” (SRS-A). They are
several times more potent than histamine in constricting
airways and promoting tissue edema formation. The
proinflammatory effect of LTE
is less than that of LTC
and LTD4; it is excreted in the urine and is used as a
marker of leukotriene production.
Antileukotriene agents, which can be used in treatment
of allergen and exercise-induced asthma and allergic rhini-
tis, inhibit 5-lipoxygenase or the binding of the activator
protein with 5-lipoxygenase or antagonists of leukotriene
receptors at the target cell (e.g., airway epithelial cell).
The traditional drugs used for treatment of asthma include
inhaled corticosteroids, /
Leukotriene receptor antagonists are orally active and are
a new class of antiasthmatic therapeutic agents (Figure
Supplemental Readings and References
A. Ascherio, M. B. Katan, P. L. Zook, et al.: Trans fatty acids and coronary
New England Journal of Medicine
340, 1994 (1999).
R. G. Boles, E. A. Buck, M. G. Blitzer, et at: Retrospective biochemical
screening of fatty acid oxidation disorders in postmortem livers of 418
cases of sudden death in the first year of life.
Journal of Pediatrics
J. M. Drazen, E. Israel, and P. M. O’ Byrne: Treatment of asthma with drugs
modifying the leukotriene pathway.
New England Journal of Medicine
340, 197 (1999).
S. Eaton, K. Bartlett, and M. Pourfarzam: Mammalian mitochondrial
320, 345 (1996).
C. J. Hawkey: COX2 inhibitors.
353, 307 (1999).
J. A. Ibdah, M. J. Bennett, P. Rinaldo, et al.: A fetal fatty-acid oxidation
disorder as a cause of liver disease in pregnant women.
Journal of Medicine
340, 1723 (1999).
S. M. Innis, H. Sprecher, D. Hachey, et al.: Neonatal polyunsaturated fatty
34, 139 (1999).
B. A. Johnson, J. D. Roache, M. A. Javors, et al.: Ondansetron for reduction
of drinking among biologically predisposed alcoholic patients.
American Medical Association
284, 963 (2000).
H. R. Kranzler: Medications for alcohol dependence—New vistas.
of American Medical Association
284, 1016 (2000).
R. G. Kurumbail, A. M. Stevens, J. K. Gierse,et al.: Structural basis for selec-
tive inhibition of cyclooxygenase-2 by anti-inflammatory agents.
D. R. Lichtenstein, M. M. Wolfe: COX2 Selective NSAIDs. New and im-
Journal of American Medical Association
284, 1297 (2000).
B. J. Lipworth: Leukotriene-receptor antagonists.
E. Mayatepek and B. Flock: Leukotriene C4-synthesis deficiency: a new
inborn error of metabolism linked to a fatal developmental syndrome.
A. A. M. Morris, S. I. Olpin, M. Brivet, et al.: A patient with carnitine-
acylcarnitine translocase deficiency with a mild phenotype.
132, 514 (1998).
P. M. O’Byme, F. Israel, and J. M. Drazen: Antileukotrienes in the treatment
Annals of Internal Medicine
M. R. Pierce, G. Pridpan, S. Morrison, and A. S. Pickoff: Fatal carnitine
palmitoyltransferase II deficiency in a newborn: New phenotypic features.
38, 13 (1999).