Metabolism of the Eicosanoids

Drugs that block prostaglandin production should _____

*provide relief from pain

Formation of Lipoxins

-15-lipoxygenase then 5-lipoxygenase then a series of reductions on arachidonic acid ---> a trihydroxy derivative of arachidonic acid known as a lipoxin

The biosynthesis of prostaglandins derived from arachidonic acid are the ___ series

-2 series (only series in substantial amounts)

cyclo-oxygenase enzyme exists in two form___ and ____.

-COX-1 = a constitutive form the enzyme, widely expressed in almost all tissues, the only form expressed in mature platelets. Involved in the production of prostaglandins and thromboxanes for "normal" physiologic function -COX-2 = an inducible form of cyclo-oxygenase regulated by cytokines and growth factors. Normally low in most healthy tissue, but are expressed at high levels in inflamed tissue

Active TXA2 is rapidly metabolized to ____, by ____

-TXB2 -cleavage of the oxygen bridge between carbons 9 and 11 to form two hydroxyl groups. TXB2 has no biologic activity.

Activation of phospholipase A2 and C

-agonist (stimuli) such as histamine and cytokines

Isoprostanes are derived from ____ by ____, initiated by _____ Isoprostane levels in the urine can be used a measure of ___

-arachidonic acid -lipid peroxidation -free radicals -it is cleaved off of a phospholipid component of the cell membrane after undergoing free radical change and is released into circulation as an eicosanoid (isoprostane) -oxidative stress **they also have some/minimal biological effects similar to PGF2a

What types of fats do diets with cold water fish have?

-eicosapentaenoic acid (EPA) = a 20C fatty acids that can synthesize the 3 series of thromboxanes (less effective in stimulating platelet aggregation that its counterpart in the 2 series, TXA2)

Synthesis of Leukotrienes, HETE, and Lipoxins

-from arachidonic acid by lipoxygenase enzymes that incorporate an oxygen molecule onto a carbon of one of several double bonds, forming a hydroperoxy group = (HPETEs)

Action of Phospholipase C

-hydrolyzes phosphorylated inositol from the inositol glycerophospholipids, generating a diacylglycerol containing arachidonic acid. This arachidonic acid is subsequently released by the action of other lipases

Where is TXA synthase present in high concentrations?

-in the platelets

Basics of eicosanoids

-include the prostaglandins (PG), thromboxanes (TX), and leukotrienes (LT) -among the most potent regulators of cellular function in nature and are produced by almost every cell in the body. -They act mainly as "local" hormones, affecting the cells that produce them or neighboring cells of a different type. **derived from polyunsaturated fatty acids containing 20 carbon atoms, which are found in cell membranes esterified to membrane phospholipids -major precursor is (20C) arachidonic acid

Action of Lipoxins

-induce chemotaxis -stimulate superoxide anion production in leukocytes

Because arachidonic acid cannot be synthesized de novo in the body; the major dietary precursor for arachidonic acid synthesis is the essential amino acid ____, which is present in ____.

-linoleate -plant oils

-NSAIDs -Aspirin -acetominophen (in motrin, Nuprin, Advil) and ibuprofen

-nonsteroidal anti-inflammatory drugs -cyclo-oxygenase inhibitors -block both isoforms (COX-1 and COX-2) -aspirin transfers an acetyl group to the enzyme IRREVERSIBLY inactivating it -acts as reversible inhibitors of cyclo-oxygenase

In vascular endothelium, PGH2 is converted to ____, by ____. what is its action____

-prostaglandin PGI2 (prostacyclin) -PGI synthase -inhibits platelet aggregation and causes vasodilation

Prostaglandins are inactivated by oxidation of ____. The double bond C13 is ____. Produces ____ that are excreted in the urine

-the 15-hydroxy group, which is critical for their activity, to a ketone -reduced -dicarboxylic acids

Phospholipase A2 is specific for ____

-the sn-2 position of phosphoacyglycerols

Main difference in structure b/w prostaglandins and thromboxanes

-thromboxanes contain a SIX membered ring that includes an oxygen atom (as opposed to a FIVE membered ring w/ two substituents)

Biosynthesis of prostaglandins and thromboxanes

1) initial step catalyzed by cyclo-oxygenase, forms the five-membered ring and adds four atoms of oxygen to form the UNSTABLE endoperoxide, PGG2 2) the hydroperoxy group at C15 is quickly reduced to a hydroxyl group by a peroxidase to form another endoperoxide, *PGH2* 3) Next step is tissue specific: PGH2 is converted to different prostaglandins or to Thromboxane TXA2 in a reaction catalyzed by TXA synthase

HPETEs 2 pathways The major leukotrienes are produced by ____. In leukocytes and mast cells, 5-HPETE is converted to an ____, ____.

1) reduced to the corresponding hydroxy metabolites, HETEs 2) metabolized to form leukotrienes or lipoxins -5-lipoxygenase (converts arachidonic acid to 5-HPETE) -epoxide -leukotriene A4 (LTA4) --->forms other functional leukotrienes in one of two pathways: 1) conversion to LTB4 2) addition of reduced glutathione to carbon 6 to form LTC4, a reaction catalyzed by glutathionine S-transferase 3) glutamate is removed from the glutathionine moiety of LTC4 through the action of y-glutamyl transpeptidase to form LTD4 4) A dipeptidase then cleaves the glycine residue from LTD4 to for LTE4