Friday 30 April 2004
Most members of this family are rapidly metabolized near their site of synthesis, so they act locally on neighboring cells, not distant parts of the body. They are also not stored in cells, but synthesized rapidly in response to stimuli, making regulation of their synthesis a key to their activity.
Many drugs act through modulating the production of eicosanoids or modulating their signaling pathways.
Arachidonic acid (AA)-derived eicosanoids belong to a complex family of lipid mediators that regulate a wide variety of physiological responses and pathological processes.
They are produced by various cell types through distinct enzymatic pathways and act on target cells via specific G-protein-coupled receptors.
Although originally recognized for their capacity to elicit biological responses such as vascular homeostasis, protection of the gastric mucosa and platelet aggregation, eicosanoids are now understood to regulate immunopathological processes ranging from inflammatory responses to chronic tissue remodelling, cancer, asthma, rheumatoid arthritis and autoimmune disorders.
Arachidonic acid has several possible fates, including oxygenation by lipoxygenases to make HPETEs (hydroperoxy-eicosatetraenoic acids), or production of prostaglandin H2 by PGH2 synthase.
5-lipoxygenase acts with the membrane bound protein FLAP (five lipoxygenase activating protein) to produce the epoxide leukotriene LTA4 which is hydrolyzed to produce LTB4 or has glutathione added by a glutathione S-transferase to produce LTC4 and LTD4. A G-protein coupled receptor for LTD4, CysLT1, mediates an important component of the inflammatory response of leukotrienes on airway constriction and recruitment of leukocytes, and several marketed asthma drugs act as antagonists of the CysLT1 receptor.
PGH2 synthase actually consists of two enzyme components, a cyclooxygenase and a peroxidase, and there are more than one type of cycloxygenase, including Cox-1 and Cox-2. Recent NSAIDS acting selectively as Cox-2 inhibitors like Vioxx are widely used for the treatment of arthritis and other inflammatory conditions, inhibiting the production of downstream thromboxanes and prostaglandins. PGH2 also has several possible fates, including conversion by thromboxane synthase to Tpx2, an eicosinoid with potent coagulation and vasoconstriction activity.
PGI2, or prostacyclin, synthesized by prostacyclin synthase, has properties opposite those of thromboxane, causing vasodilation and a reduction in clotting through the IP receptor, causing thromboxanes and PGI2 to act in opposition to each other. Thromboxane antagonists and prostacyclin agonists both provide tools and drugs to reduce vasoconstriction.
The prostaglandins include PGD2, PGE2 and PGF2, with varying degrees of selectivity among their receptors, DP, EP and FP, respectively. PGE2 exerts biological effects including induction of pain, fever and vasodilation through at least four receptors, EP1, EP2, EP3 and EP4, and EP3 is found in multiple splice variants.
- regulation of vasodilation
- vascular permeability
- recruitment of leukocytes