Quantitative Analysis of Cyclooxygenase Metabolites of Arachidonic Acid
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Metabolism of arachidonic acid results in a host of biologically active compounds with profound effects on airway inflammation (
1
). After activation of cellular phospholipases and release of free arachidonic acid, catalyzed insertion of oxygen occurs enzymatically via action of one of the two known cyclooxygenase isoenzymes (COX-1 and COX-2). The unstable bicyclic intermediate, PGH
2
, undergoes subsequent metabolism to form prostaglandins (PG), thromboxane (Tx), and leukotrienes (LT) (
see
Fig.1 ). In addition, free radicals can oxygenate arachidonate although it is bound to the diacylgycerol backbone of membrane phospholipids. The family of compounds formed in this way, known as isoprostanes, are stereochemically different and incorporate a large number of regioisomeric compounds that may confound measurement of PG (
2
–
5
and
see
Chapter 33 ). Arachidonic acid can also be metabolized by specific cytochrome P
450
enzymes to regioisomeric epoxides and stereo specific hydro xyeicosatetraenoic (HETE) acids (
6
).
Fig. 1.
Overview of pathways of metabolism of arachidonic acid during airway inflammation. Following activation of cellular phospholipases, arachidonic acid is cleaved from membrane phospholipids. It is undergoing dioxygenation catalyzed by cyclooxygenase (either COX-1 or COX-2 isoforms) to form the unstable endoperoxide intermediate PGH2. Specific isomerases with varied cellular distribution further metabolize PGH2 to bioactive prostaglandins and thromboxanes
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