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Archanoid Acid Affect Cox

FIGURE 25-1 Metabolism of arachidonic acid. The cyclooxygenase (COX) pathway is highlighted in gray. The lipoxygenase (LOX) pathways are expanded in Figure 25-2. Cyclic endoperoxides (PGG2 and PGH2) arise from the sequential cyclooxygenase and hydroperoxidase actions of COX-1 or COX-2 on arachidonic acid released from membrane phospholipids. Subsequent products are generated by tissue-specific synthases and transduce their effects via membrane-bound receptors (gray boxes). Dashed lines indicate putative ligand-receptor interactions. EETs (shaded in blue) and isoprostanes are generated via CYP activity and nonenzymatic free radical attack, respectively. COX-2 can use modified arachidonoylglycerol, an endocannabinoid, to generate the glyceryl prostaglandins. Aspirin and tNSAIDs are nonselective inhibitors of COX-1 and COX-2 but do not affect LOX activity. Epilipoxins are generated by COX-2 following its acetylation by aspirin (Figure 25-2). Dual 5-LOX-COX inhibitors interfere with both pathways. See text for other abbreviations.

FIGURE 25-1 Metabolism of arachidonic acid. The cyclooxygenase (COX) pathway is highlighted in gray. The lipoxygenase (LOX) pathways are expanded in Figure 25-2. Cyclic endoperoxides (PGG2 and PGH2) arise from the sequential cyclooxygenase and hydroperoxidase actions of COX-1 or COX-2 on arachidonic acid released from membrane phospholipids. Subsequent products are generated by tissue-specific synthases and transduce their effects via membrane-bound receptors (gray boxes). Dashed lines indicate putative ligand-receptor interactions. EETs (shaded in blue) and isoprostanes are generated via CYP activity and nonenzymatic free radical attack, respectively. COX-2 can use modified arachidonoylglycerol, an endocannabinoid, to generate the glyceryl prostaglandins. Aspirin and tNSAIDs are nonselective inhibitors of COX-1 and COX-2 but do not affect LOX activity. Epilipoxins are generated by COX-2 following its acetylation by aspirin (Figure 25-2). Dual 5-LOX-COX inhibitors interfere with both pathways. See text for other abbreviations.

AA is metabolized successively to the cyclic endoperoxide prostaglandins G (PGG) and H (PGH) (Figure 25-1) by the cyclooxygenase (COX) and hydroperoxidase (HOX) activities of the prostaglandin G/H synthases. Isomerases and synthases effect the transformation of PGH2 into terminal prostanoids distinguished by substitutions on their cyclopentane rings.

Prostaglandins of the E and D series are hydroxyketones, whereas the Fa prostaglandins are 1,3-diols (Figure 25-1). A, B, and C prostaglandins are unsaturated ketones that arise nonenzy-matically from PGE during extraction procedures; it is unlikely that they occur biologically. PGJ2 and related compounds result from the dehydration of PGD2. Prostacyclin (PGI2) has a doublering structure; in addition to a cyclopentane ring, a second ring is formed by an oxygen bridge between carbons 6 and 9. Thromboxanes (Txs) contain a six-member oxirane ring instead of the cyclopentane ring of the prostaglandins. The main classes are further subdivided in accord with the number of double bonds in their side chains, as indicated by numerical subscripts. Dihomo-g-linolenic acid is the precursor of the one series, AA for the two series, and EPA for the three series. Prostanoids derived from AA carry the subscript 2 and are the major series in mammals. There is little evidence that one- or three-series prostanoids are made in adequate amounts to be important under normal circumstances. However, the health benefits of dietary supplementation with m-3 fatty acids remain a focus of investigation.

Synthesis of prostanoids is accomplished in a stepwise manner by a complex of microsomal enzymes. The first enzyme in this synthetic pathway is prostaglandin endoperoxide G/H synthase, which is colloquially called cyclooxygenase, or COX. There are two distinct COX isoforms, COX-1 and COX-2. COX-1 is expressed constitutively in most cells, whereas COX-2 is up-regulated by cytokines, shear stress, and growth factors. Thus, COX-1 is considered to subserve housekeeping functions such as cytoprotection of the gastric epithelium (see Chapter 36). COX-2 is the major source of prostanoids formed in inflammation and cancer. This distinction is overly simplistic: there are physiological and pathophysiological processes in which each enzyme is uniquely involved and others in which they function coordinately.

Products of Lipoxygenases

Lipoxygenases (LOXs) are a family of non-heme iron-containing enzymes that catalyze the oxygenation of polyenic fatty acids to corresponding lipid hydroperoxides. The enzymes require a fatty acid substrate with two cis double bonds separated by a methylene group. AA, which contains several double bonds in this configuration, is metabolized to hydroperoxy eicosatetraenoic acids (HPETEs), which vary in the site of insertion of the hydroperoxy group. Analogous to PGG2 and PGH2, these unstable intermediates are further metabolized by a variety of enzymes. HPETEs are converted to their corresponding hydroxy fatty acid (HETE) either nonenzymatically or by a peroxidase.

The 5-LOX pathway leads to the synthesis of the leukotrienes (LTs), which play a major role in the development and persistence of the inflammatory response (Figure 25-2). A nomenclature (LTB4, LTB5, etc.) similar to that of prostanoids applies to the subclassification of the LTs. When eosinophils, mast cells, polymorphonuclear leukocytes, or monocytes are activated, 5-LOX translocates to the nuclear membrane and associates with 5-LOX-activating protein (FLAP), an integral membrane protein essential for LT biosynthesis. FLAP may act as an AA transfer protein that presents the substrate to the 5-LOX. A two-step reaction is catalyzed by 5-LOX: oxygenation of AA at C-5 to form 5-HPETE, followed by dehydration of 5-HPETE to an unstable 5,6-epoxide known as LTA4. LTA4 is transformed into bioactive eicosanoids by multiple pathways depending on the cellular context: transformation by LTA4 hydrolase to a 5,12-dihydroxyeicosatetraenoic acid known as LTB4; conjugation with reduced glutathione by LTC4 synthase, in eosinophils, monocytes, and mast cells, to form LTC4; and extracellular metabolism of the peptide moiety of LTC4, leading to the removal of glutamic acid and subsequent cleavage of glycine, to generate LTD4 and LTE4, respectively. LTC4, LTD, and LTE4, the cysteinyl leukotrienes, were known originally as the slow-reacting substance of anaphylaxis (SRS-A; see Chapter 27). LTB4 and LTC4 are actively transported out of the cell.

Products of CYPs P450

Multiple CYPs metabolize arachidonic acid. For instance, epoxyeicosatrienoic acids (EETs) can be formed by CYP epoxygenases, primarily CYP2C and CYP2J. Their biosynthesis can be altered by pharmacological, nutritional, and genetic factors that affect CYP expression (see Chapter 3).

EETs are important modulators of cardiovascular and renal function. They are synthesized in endothelial cells and cause vasodilation in a number of vascular beds by activating the large conductance Ca2+-activated K+ channels of smooth muscle cells. This results in hyperpolarization of smooth muscle and thus relaxation, leading to reduced blood pressure. Substantial evidence

CysLT"! CysLT2

BLT« BLTj

FIGURE 25-2 Lipoxygenase pathways of arachidonic acid metabolism. FLAP presents arachidonic acid to 5-LOX, leading to the generation of the LTs. Cysteinyl LTs are shaded in gray. Lipox-ins (shaded in blue) are products of cellular interaction via a 5-LOX-12-LOX pathway or via a 15-LOX-5-LOX pathway. Biological effects are transduced via membrane-bound receptors (dark gray boxes). Dashed line indicates putative ligand-receptor interactions. Zileuton inhibits 5-LOX but not the COX pathways (expanded in Figure 25-1). Dual 5-LOX-COX inhibitors interfere with both pathways. CysLT antagonists prevent activation of the CysLTj receptor. See text for abbreviations.

CysLT"! CysLT2

BLT« BLTj

FIGURE 25-2 Lipoxygenase pathways of arachidonic acid metabolism. FLAP presents arachidonic acid to 5-LOX, leading to the generation of the LTs. Cysteinyl LTs are shaded in gray. Lipox-ins (shaded in blue) are products of cellular interaction via a 5-LOX-12-LOX pathway or via a 15-LOX-5-LOX pathway. Biological effects are transduced via membrane-bound receptors (dark gray boxes). Dashed line indicates putative ligand-receptor interactions. Zileuton inhibits 5-LOX but not the COX pathways (expanded in Figure 25-1). Dual 5-LOX-COX inhibitors interfere with both pathways. CysLT antagonists prevent activation of the CysLTj receptor. See text for abbreviations.

indicates that EETs may function as endothelium-derived hyperpolarizing factors (EDHFs), particularly in the coronary circulation.

Other Pathways

The isoeicosanoids, a family of eicosanoid isomers, are formed nonenzymatically by direct free radical—based attack on AA and related lipid substrates. Unlike eicosanoids, these compounds are generated initially on the esterified lipid in cell membranes, from which they are cleaved, presumably by phospholipases; the free isoeicosanoids circulate and are excreted in urine. Consequently, their production is not blocked in vivo by agents that suppress metabolism of free arachidonate, such as inhibitors of COX-1 or COX-2. Since several isoprostanes can activate prostanoid receptors, it has been speculated that they may contribute to the pathophysiology of inflammatory responses in a manner insensitive to COX inhibitors.

INHIBITORS OF EICOSANOID BIOSYNTHESIS A number of the biosynthetic steps just described can be inhibited by drugs. Inhibition of phospholipase A2 decreases the release of the precursor fatty acid and thus the synthesis of all its metabolites. Since phospholipase A2 is activated by Ca2+ and calmodulin, it may be inhibited by drugs that reduce the availability of Ca2+. Glucocorticoids also inhibit phospholipase A2, but they appear to do so indirectly by inducing the synthesis of a group of proteins termed annexins (formerly lipocortins) that modulate phospholipase A2 activity (see Chapter 59). Glucocorticoids also down-regulate induced expression of COX-2 but not of COX-1. Aspirin and tNSAIDs were found originally to prevent the synthesis of prostaglandins from AA in tissue homogenates. It now is known that these drugs inhibit the COX but not the HOX moieties of the prostaglandin G/H synthases and thus the formation of their downstream prostanoid products. These drugs do not inhibit LOXs and may result in increased formation of LTs by shunting of substrate to the lipoxygenase pathway.

COX-1 and COX-2 differ in their sensitivity to inhibition by certain anti-inflammatory drugs. This observation has led to the recent development of agents that selectively inhibit COX-2, including the coxibs (see Chapter 26). These drugs were predicted to offer advantages over NSAIDs because COX-2 is the predominant cyclooxygenase at sites of inflammation, whereas COX-1 is the major source of cytoprotective prostaglandins in the GI tract. The matter is not settled, but the antiinflammatory actions of the coxibs were associated with improved GI safety compared with their nonselective counterparts in at least one trial of clinical outcomes. However, the withdrawal of rofe-coxib (vioxx) from the market because of an association in postmarketing studies with an increased risk of myocardial infarction, which may be present long after the drug is discontinued, leaves the therapeutic benefit of the COX-2-specific inhibitors in question (see Chapter 26).

Since leukotrienes mediate inflammation, efforts have focused on development of leukotriene-receptor antagonists and selective inhibitors of the LOXs. Zileuton, an inhibitor of 5-lipoxygenase, was marketed in the U.S. for the treatment of asthma but has been withdrawn. In addition, cys-teinyl leukotriene-receptor antagonists, including zafirlukast, pranlukast, and montelukast, have established efficacy in the treatment of asthma (see Chapter 27). A common polymorphism in the gene for LTC4 synthase that correlates with increased LTC4 generation is associated with aspirin-intolerant asthma and with the efficacy of antileukotriene therapy. Interestingly, while polymorphisms in the genes encoding 5-LOX or FLAP do not appear to be linked to asthma, studies have demonstrated an association of these genes with myocardial infarction, stroke, and atherosclerosis; thus, inhibition of LT biosynthesis may be useful in the prevention of cardiovascular disease.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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