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40 Cards in this Set
- Front
- Back
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What are eicosanoids?
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A catch-all phrase to encompass the diverse lipid autacoids derived from 20-carbon fatty acid precursors.
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Describe arachidonic acid
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It is a 20 carbon polyunsaturated fatty acid that is the most abundant precursor of the eicosanoids. It is an "essential fatty acid" which means humans cannot synthesize it de novo.
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Describe eicosanoid synthesis
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They are not stored, but synthesized as needed. The first step is phospholipase-mediates release of AA stored in membrane phospholipids.
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What are the posible pathways for free AA?
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-Reincoporation into the storage form phospholipid
-Oxygenation by prostaglandin G/H endoperoxide synthase (trivial name cyclooxygenase) yielding PH -Oxygenation by lipoxygenase yielding hydroperoxy acids and LT. |
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What determines the ultimate products from AA?
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The enzymatic complement of the tissue in question as well as the specific initiating stimulus
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What are the two isoforms of cyclooxygenase?
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COX I
COX II |
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Describe COX I
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It is ubiquitous and constitutively expressed. This enzyme is presumed to generate PG which play a role in homeostasis.
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Describe COX II
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COX II is an inducible form of the enzyme which is rapidly produced and rapidly degraded after cells are exposed to several cytokines or growth factors. PG generated by COX II are though to play a role in inflammation.
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What is the rate-limiting step in prostaglandin synthesis?
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The release of AA from the membrane phospholipid pool by phospholipase.
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What is the final product of the cyclooxygenase pathway in vascular tissue? What is its halflife?
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Prostacyclin (PGI2) is formed by prostacyclin synthase. PGI2 has a half-life of 3 min.
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What is the final product of the cyclooxygenase pathway in platelets and lung? What is its halflife?
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Thromboxane A2 (TXA2) is formed by thromboxane synthase. PGI2 has a half-life of 30 seconds min.
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What is the final product of the cyclooxygenase pathway in brain and mast cells?
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PGD2 is formed by isomerase
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What is the final product of the cyclooxygenase pathway in most tissues?
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PGE2 and/or PGF2alpha are formed enzymatically or nonenzymatically
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Describe lipoxygenases
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They are primaryly cytosolic enzymes which insert molecular oxygen into the fatty acid backbone yielding a hydroperoxide (HPETE). Lipoxygenases are very widespread phylogenetically and are importrant in plants as well as in animals (from coral to human). This family inducled enzymes with varying substrate specigicities and which insrt oxygen at different sites in the backbone (but always at a double bond).
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What are the well characterized lipoxygenases in humans?
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5-LO in white cells
12-LO in platelets 15-LO in macrophage and epithelium |
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What is the most important lipoxygenase in human disease? What does it do?
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5-lipoxygenase which initiates the synthesis of the leukotrienes. In a concerted two-step reaction, this enzyme converts AA into the unstable epoxide, LTA4.
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What is the halflife of LTA4?
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LTA4 has a half-life of a few seconds although in the presence of albumin it is stabilized and can persist for hours.
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Describe LTA4 as a branch point
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LTA4 is a branch point in leukotriene synthesis and can be further metabolized to LTB4 (a dihydroxy acid) or LTC4 (a peptidolipid). The conversion of LTA4 to the final biologically active produce is probably rate-limiting for the lipoxygenase pathway.
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What is LTB4? How is it generated?
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LTB4 is generated by the action of LTA4 hydrolase. This enzyme appears to be ubiquitous and this it is often found in cells which lack 5-LO.
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What is the most important source of LTB4 in humans?
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Neutrophils
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How is LTC4 generated?
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LTC4 is generated by the addition of lutathione (GSH) to LTA4 forming a peptidolipid. LTC4 synthase which catalyzes this reaction is distinct from the general class of glutathione-S-transferases.
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What is LTC4 converted into?
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In many tissues, LTC4 is rapidly converted to LTD4 by the action of gamma-glutamyl transpeptidase which cleaves glutamate from the GSH side chain. LTC4 and LTD4 have equally important biological activity.
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Describe the metabolism of stable PG PGE2, and PGF2alpha.
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These are mostly metabolized to the 15-keto deriveative by prostaglandin 15-hydroxy dehydrogenase (PGDH). Nearly all of the PG are cleared by a single pass through the pulmonary circualtion (PGI2 is a notable exception) although PGDH is also found in the spleen and renal cortex. Ultimately, beta oxidation products are excreted in the urine.
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Describe the metabolism of PGI2 and TXA2.
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PGI2 and TXA2 spontaneously degrade to the biologically inactive compounds, 6-keto-PGF1alpha and TXB2, respectively. These metabolites also undergo beta oxidation and end up in the urine.
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Describe the metabolism of LTB4.
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LTB4 can be metabolized by omega oxydation.
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Describe the metabolism of LTC4.
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LTC4 is converted to LTD4. LTD4 is converted by a second peptidase to LTE4, which is much less active than its two precursors. LTE4 is ultimately acetylated, omgea oxidized and excreted.
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What is the mechanism of action for prostaglandins and leukotrienes?
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PG and leukotrienes bind to specific receptors and mediate their effects through the generation of intracellular second messengers. Numerous receptors have been cloned and others are classified pharmacologically. This is an active area of research interest and new clinical tools will likely become available in the future.
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What are the agonists, 2nd messengers, and targets with the receptor IP?
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Agonist: PGI2, PGE1
2nd Messenger:Increase cAMP Target(s): platelets (disaggregation), vascular, pulmonary, uterine smooth muscle |
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What are the agonists, 2nd messengers, and targets with the receptor EP1?
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Agonist: PGE2
2nd Messenger: PLC Target(s): Smooth muscle contraction |
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What are the agonists, 2nd messengers, and targets with the receptor EP2?
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Agonist: PGE2, misoprostol
2nd Messenger: increase cAMP Target(s): platelets, smooth muscle relaxation, fertilization |
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What are the agonists, 2nd messengers, and targets with the receptor EP3?
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Agonist: PGE2, misoprostol
2nd Messenger: decrease cAMP Target(s): gastric acid secretion, kidney?, nervous system, induction of fever |
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What are the agonists, 2nd messengers, and targets with the receptor EP4?
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Agonist: PGE2
2nd Messenger: increased cAMP Target(s): closure of the ductus, arteriosis, bone formation |
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What are the agonists, 2nd messengers, and targets with the receptor FP?
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Agonist: PGF2alpha
2nd Messenger: PLC Target(s): smooth Smooth muscle contraction, induction of labor |
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What are the agonists, 2nd messengers, and targets with the receptor DP?
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Agonist: PGD2
2nd Messenger: increased cAMP Target(s): platelets, granulocytes, nervous system, mucus secretion |
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What are the agonists, 2nd messengers, and targets with the receptor TPa?
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Agonist: TXA2, PGG2/H2
2nd Messenger: PLC Target(s): platelets (aggregation) |
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What are the agonists, 2nd messengers, and targets with the receptor TPs?
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Agonist: TXA, PGG2/H2
2nd Messenger: PLC Target(s): Vascular, pulmonary, smooth muscle |
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What are the agonists, 2nd messengers, and targets with the receptor BLT1?
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Agonist: LTB4
2nd Messenger: PLC, decrease cAMP Target(s): leukocytes |
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What are the agonists, 2nd messengers, and targets with the receptor BLT2?
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Agonist: LTB4
2nd Messenger: PLC, decreased cAMP Target(s): spleen, liver, ovary |
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What are the agonists, 2nd messengers, and targets with the receptor cysLT1?
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Agonist: LTD4, LTE4
2nd Messenger: PLC Target(s): Peripheral blood leukocytes, smooth muscle, especially in the lung |
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What are the agonists, 2nd messengers, and targets with the receptor cysLT2?
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Agonist: LTC4, LTD4
2nd Messenger: PLC Target(s): Macrophages, airway smooth muscle, cardiac Purkinje cells, adrenal medulla brain |
