Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.13.11.12 (lipoxygenase)
8,696 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hypothesis that endothelium-dependent components contribute to the cerebromicrovascular dilation to hypoxia in the newborn pig was addressed. Piglets anesthetized with ketamine-acepromazine and maintained on alpha-chloralose were equipped with closed cranial windows. Injury to the endothelium of pial arterioles was produced by light activation of fluorescein dye. Light/dye injury reduced the pial arteriolar dilation to hypoxia (5 min, arterial PO2 approximately 30 mmHg) from 57 +/- 9 to 19 +/- 5%. Light/dye injury abolished the pial arteriolar dilation to hypercapnia but did not affect dilation to sodium nitroprusside. The pial arteriolar dilation to hypoxia was not affected by tetrodotoxin, N(omega)-nitro-L-arginine, glibenclamide, iberiotoxin, charybdotoxin, tetraethylammonium, or 8-phenyltheophylline. Hypoxia caused increases in the cerebral cortical production of adenosine 3',5'-cyclic monophosphate and guanosine 3',5'-cyclic monophosphate. Cerebral vasodilation to hypoxia was inhibited by 5,8,11,14-eicosatetraynoic acid but was not greatly affected by cyclooxygenase or lipoxygenase inhibitors. In contrast, the cytochrome P-450 epoxygenase inhibitor miconazol decreased cerebral vasodilation to hypoxia from 45 +/- 5 to 17 +/- 4%. Therefore, the vascular endothelium appears to participate in cerebral microvascular dilation to hypoxia in newborn pigs. The mechanism may include cytochrome P-450 epoxygenase metabolites of arachidonic acid.
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PMID:Mechanisms of hypoxia-induced cerebrovascular dilation in the newborn pig. 908 8

Voltage-gated rat skeletal muscle and cardiac Na+ channels are modulated by exogenous unsaturated fatty acids. Application of 1-10 microM arachidonic or oleic acids reversibly depressed Na+ channel conductance and shifted the inactivation curve to hyperpolarizing potentials. These effects were not prevented by inhibitors of lipoxygenase, cyclooxygenase, cytochrome P-450 epoxygenase, or protein kinase C. Neither palmitic acid nor methyl ester oleate had an effect on the inward Na+ current, suggesting that trivial variations in membrane fluidity are not responsible for the Na+ current depression or kinetic changes. Arachidonic acid altered fast Na+ inactivation without changing the slow inactivation kinetics. Moreover, skeletal muscle Na+ channel gating currents were markedly decreased by 2 microM arachidonic acid. Finally, nonstationary noise analysis indicated that both the number of channels and the open probability were slightly decreased without change in the single-channel conductance. These data suggest that unsaturated fatty acids such as arachidonic and oleic acids 1) specifically regulate voltage-gated Na+ channels and 2) interact directly with Na+ channels, perhaps at a fatty acid binding domain, by decreasing the total gating charge and altering fast-inactivation kinetics.
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PMID:Mechanism of modulation of the voltage-gated skeletal and cardiac muscle sodium channels by fatty acids. 912 3

In an attempt to determine the chemosensory cues, if any, provided by fats in the oral cavity, we have performed patch-clamp recordings on isolated rat taste receptor cells during application of free fatty acids. Cis-polyunsaturated fatty acids, when applied extracellularly, inhibit delayed-rectifying K+ channels. In a subset of cells, these fatty acids also enhance inwardly rectifying K+ currents. Saturated, monounsaturated, and trans-polyunsaturated fatty acids have no significant effect on K+ currents. These effects do not involve activation of G protein-mediated pathways, including protein kinase C and protein kinase A, lipoxygenase pathways, cyclooxygenase pathways, or cytochrome P-450 pathways, consistent with direct effects on these ion channels or closely associated proteins. The net effect of fatty acids is to prolong stimulus-induced depolarizations of taste receptor cells, and we propose the effects on K+ channels represent the mechanism by which fats are detected by receptor cells in the oral cavity.
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PMID:Fatty acid modulation of K+ channels in taste receptor cells: gustatory cues for dietary fat. 914 45

The mechanism by which nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, prevents swelling-activated organic osmolyte efflux was examined in the human hepatoma cell line Hep G2. When swollen in hypotonic medium, Hep G2 cell exhibited a regulatory volume decrease that was associated with the release of intracellular taurine, an amino acid found at a concentrations of 22.0 +/- 2.5 nmol/mg protein (approximately 5 mM) in these cells. Rate coefficients for swelling-activated [3H]taurine uptake and efflux were unaffected when extracellular taurine was increased from 0.1 to 25 mM, indicating that taurine is released via a channel. Taurine efflux was rapidly activated after cell swelling and immediately inactivated when cells were returned to normal size by restoration of isotonicity. Swelling-activated taurine efflux was not altered by replacement of extracellular Na+ with choline+ or K+ but was inhibited when cellular ATP levels were decreased with a variety of chemical agents, consistent with an ATP-regulated channel previously described in other cell types. NDGA inhibited swelling-activated [3H]taurine efflux in Hep G2 cells at concentrations of 50-150 microM; however, these same concentrations of NDGA also lowered cell ATP levels. Likewise, ketoconazole, an inhibitor of cytochrome P-450 monoxygenases, inhibited [3H]taurine efflux only at concentrations at which cell ATP levels were also lowered. In contrast, other inhibitors of cyclooxygenase (indomethacin, 100 microM) or of lipoxygenases (caffeic acid, 100 microM), as well as arachidonic acid itself (100 microM), had no effect on either taurine efflux or cell ATP. The present findings characterize a swelling-activated, ATP-sensitive osmolyte channel in Hep G2 cells and demonstrate that inactivation of the channel by NDGA is related to the ability of this drug to deplete cellular ATP.
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PMID:Nordihydroguaiaretic acid depletes ATP and inhibits a swelling-activated, ATP-sensitive taurine channel. 917 31

In the rat isolated perfused kidney, 5,8,11,14-eicosatetraynoic acid, an inhibitor of all pathways of arachidonic acid (AA) metabolism, diminished endothelin-1 (ET-1)- and angiotensin II (ANG II)-induced renal vasoconstriction by approximately 60-70%. We then examined the individual contribution of each oxygenase, cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P-450 (CYP) to the vasoconstrictor effects of ET-1 and ANG II. Inhibition of COX with indomethacin reduced by 30-40% the vasoconstrictor responses to ET-1 and ANG II. Inhibition of 12-LOX with baicalein and 5- and 12-LOX with 5,8,11-eicosatriynoic acid attenuated ANG II-induced renal vasoconstriction by approximately 40-60% but did not affect responses to ET-1. In contrast, 12,12-dibromododec-11-enoic acid (DBDD), an inhibitor of the CYP omega/omega 1-hydroxylase pathway, diminished ET-1-induced renal vasoconstriction by 30-40%, an effect reproduced by depletion of CYP enzymes with CoCl2. Neither DBDD nor CoCl2 affected renal vasoconstriction elicited by ANG II. ET-1 increased efflux of 19- and 20-hydroxyeicosatetraenoic acid, an effect reduced by DBDD. Thus products of the COX and CYP pathways contribute to the renal vasoconstrictor response to ET-1, whereas COX- and LOX-derived eicosanoids contribute to the response to ANG II, accounting for > or = 80% of the vasoactivity of the peptides.
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PMID:Renal oxygenases: differential contribution to vasoconstriction induced by ET-1 and ANG II. 924 63

We examined whether metabolites of arachidonic acid (AA) regulate K+ efflux during regulatory volume decrease (RVD) by mudpuppy red blood cells (RBCs). Volume regulation was inhibited by the phospholipase A2 antagonists mepacrine (10 microM) and ONO-RS-082 (10 microM); the inhibitory effect of ONO-RS-082 was reversed by gramicidin (5 microM). Eicosatetraynoic acid (ETYA, 100 microM), a general antagonist of AA metabolism, also blocked RVD. In addition, volume regulation was inhibited by the lipoxygenase pathway antagonist nordihydroguaiaretic acid (NDGA, 10 microM), the 5 lipoxygenase antagonists AA-861 (5 microM) and curcumin (20 microM), and by the 5-lipoxygenase activating protein inhibitor L-655,298 (5 microM). Inhibition by all four of these agents was reversed with gramicidin. In contrast, the 12- and 15-lipoxygenase pathway inhibitor ethyl-3,4-dihydroxy-benzylidene-cyanoacetate (EDBCA, 1 microM) and the cytochrome P-450 monooxygenase pathway blocker ketoconazole (20 microM) had no effect. On the other hand, the cyclooxygenase pathway inhibitor aspirin (100 microM) slightly enhanced RVD. Consistent with these findings, a K(+)-selective whole cell conductance responsible for K+ efflux during cell swelling was inhibited by ONO-RS-082 (10 microM), NDGA (10 microM), AA-861 (5 microM), curcumin (20 microM), and L-655,298 (5 microM). In contrast, EDBCA (1 microM), ketoconazole (20 microM), and indomethacin (10 microM) did not block this whole cell conductance. These results indicate that a channel mediating K+ loss during RVD is regulated by a 5-lipoxygenase metabolite of arachidonic acid.
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PMID:5-Lipoxygenase metabolites of arachidonic acid regulate volume decrease by mudpuppy red blood cells. 926 85

Activation of angiotensin receptors activates phospholipase A2 (PLA2) in various tissues, resulting in the release of arachidonic acid and formation of vasoactive metabolites. The present study examined the role of the lipoxygenase and cytochrome P-450 pathways by evaluating the effects of PLA2, cyclooxygenase, lipoxygenase, and epoxygenase inhibition on the afferent arteriolar responses to angiotensin II (ANG II) and norepinephrine in the vitro perfused rat juxtamedullary nephron preparation. ANG II (0.01-100 nM) resulted in a dose-dependent afferent arteriolar vasoconstriction ranging from 3 +/- 1 to 32 +/- 2% (n = 47). Norepinephrine at 0.01, 0.1, and 1.0 microM also decreased afferent arteriolar diameter by 5 +/- 1, 17 +/- 1, and 34 +/- 2%, respectively (n = 43). In the presence of arachidonyl trifluoromethyl ketone (AACOCF3, 20 microM), a PLA2 inhibitor, afferent arteriolar vasoconstriction to ANG II (100 nM) was attenuated, and the diameter decreased by 23 +/- 4% (n = 7). The cyclooxygenase inhibitor, indomethacin (10 microM), and the cyclooxygenase-2 inhibitor, NS-398 (10 microM), did not affect the afferent arteriolar response to ANG II. The lipoxygenase inhibitor biacalein (1 microM) attenuated the afferent arteriolar response to ANG II, and vessel diameter decreased by 11 +/- 5% (n = 6) in response to 100 nM ANG II. On the other hand, miconazole (1 microM), a selective epoxygenase inhibitor, enhanced the afferent arteriolar vasoconstriction to 100 nM ANG II. 17-Octadecynoic acid (17-ODYA, 1 microM), an inhibitor of hydroxylase and epoxygenase metabolism of arachidonic acid, also increased the responsiveness of the afferent arteriole. PLA2, lipoxygenase, or cytochrome P-450 inhibition had no effect on the afferent arteriolar vasoconstriction to norepinephrine. The afferent arteriolar vasoconstrictor response to norepinephrine (0.1 microM) was enhanced by indomethacin or NS-398, and diameter decreased by 25 +/- 3% and 28 +/- 4%, respectively. Results of this study suggest that metabolites of the cyclooxygenase pathway attenuate the afferent arteriolar vasoconstrictor effect of norepinephrine. Furthermore, these data suggest that activation of PLA2 is involved in part of the afferent arteriolar response to ANG II and that metabolites of the lipoxygenase pathway augment and metabolites of the epoxygenase pathway attenuate the afferent arteriolar vasoconstrictor effect of ANG II.
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PMID:Afferent arteriolar responses to ANG II involve activation of PLA2 and modulation by lipoxygenase and P-450 pathways. 927 88

Depletion of Ca2+ pools using the irreversible Ca2+ pump blocker, thapsigargin, induces DDT1MF-2 smooth muscle cells to enter a stable nonproliferative state. Reversal of this state can be mediated by high (20%) serum treatment, which induces new Ca2+ pump protein, return of Ca2+ pools, and reentry of cells into the cell cycle; the effect of serum can be mimicked by the essential fatty acids (EFA), arachidonic, linoleic, and alpha-linolenic acids (Graber, M.N., Alfonso, A., and Gill, D.L., (1996) J. Biol. Chem. 271, 883-888). The possible requirement for EFA metabolism in inducing recovery of Ca2+ pool-depleted growth-arrested cells was investigated. Neither cyclooxygenase or lipoxygenase inhibitors had any effect on arachidonic acid-induced growth recovery of thapsigargin-treated cells. In contrast, the cytochrome P-450 epoxygenase inhibitors, SKF525A and metyrapone, substantially reduced arachidonic acid-induced recovery of growth while having minimal effects on control cell growth. Both epoxygenase inhibitors completely prevented the arachidonic acid-induced recovery of bradykinin-releasable Ca2+-pumping pools, whereas cyclooxygenase and lipoxygenase inhibitors had no effect. The effectiveness of the four cytochrome P-450 metabolites of arachidonic acid on recovery of Ca2+ pools were compared; 8,9- and 11,12-epoxyeicosatrienoic acid (EET) at 1.5 microM were completely effective in recovering agonist-sensitive Ca2+ pools, whereas the 5,6- and 14,15-EETs were without effect. SKF525A did not block the action of 8,9- or 11, 12-EET indicating further P-450 metabolism was not required. Hydration of the active EET molecules prevented Ca2+ pool recovery since the dihydroxy-derivatives of both 8,9- and 11,12-EET were ineffective. The specificity of effectiveness among EET molecules for subsequent resumption of growth of thapsigargin-treated cells was the same as for Ca2+ pool recovery. Significantly, the P-450 inhibitors, SKF525A and metyrapone, both prevented the action of 20% serum in inducing recovery of thapsigargin-treated cells, whereas cyclooxygenase and lipoxygenase inhibitors were ineffective, indicating that EFAs are the active component within serum that is responsible for recovery of Ca2+ pool-depleted cells. The specific action of EETs in mediating recovery of Ca2+ pools and growth of thapsigargin-treated cells represents not only a novel action of epoxygenase products from EFAs, but also a potentially significant new signaling pathway that may effect translational control and regulate transition from a stationary to proliferative growth state.
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PMID:Recovery of Ca2+ pools and growth in Ca2+ pool-depleted cells is mediated by specific epoxyeicosatrienoic acids derived from arachidonic acid. 936 16

Norepinephrine (NE) stimulates release of arachidonic acid (AA) from tissue lipids in blood vessels, which is metabolized via cyclooxygenase, lipoxygenase (LO), and cytochrome P-450 (CYP-450) pathways to biologically active products. Moreover, NE and AA have been shown to stimulate proliferation of vascular smooth muscle cells (VSMCs) of rat aorta. The purpose of this study was to determine the possible contribution of AA and its metabolites to NE-induced mitogenesis in VSMCs of rat aorta and the underlying mechanism of their actions. NE (0.1 to 10 micromol/L) increased DNA synthesis as measured by [3H]thymidine incorporation in VSMCs, and this effect was attenuated by inhibitors of CYP-450 (17-octadecynoic acid, 5 micromol/L; 12-diabromododec-11-enoic acid, 10 micromol/L; and dibromo-dodecenyl-methylsulfimide, 10 micromol/L) and by the LO inhibitor (baicalein, 20 micromol/L), but not by the cyclooxygenase inhibitor (indomethacin, 5 micromol/L). CYP-450 and LO metabolites of AA, 20-hydroxyeicosatetraenoic acid (HETE) (0.1 to 0.5 micromol/L) and 12(S)-HETE, respectively, increased [3H]thymidine incorporation in VSMCs. Both NE and 20-HETE increased mitogen activated protein (MAP) kinase activity as measured by the in-gel kinase assay. The inhibitor of MAP kinase kinase, PD-98059 (50 micromol/L), attenuated NE as well as 20-HETE induced [3H]thymidine incorporation and MAP kinase activation in VSMCs. These data suggest that products of AA formed via CYP-450, most likely 20-HETE, and via LO mediate NE induced mitogenesis in VSMCs.
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PMID:Cytochrome P-450 metabolites mediate norepinephrine-induced mitogenic signaling. 945 10

Whole-cell patch-clamp recordings were used to investigate the effects of arachidonic acid (AA) on K+ and Ca2+ channels in isolated rat type I carotid body cells. AA (2-20 microM) produced a concentration-dependent inhibition of both K+ currents and Ca2+ channel currents. The effects of AA on K+ currents were unaffected by indomethacin (5 microM), phenidone (5 microM) or 1-aminobenzotriazole (3 mM), suggesting that AA did not exert its effects via cyclo-oxygenase, lipoxygenase or cytochrome P-450 (cP-450) metabolism. Our results suggest that AA directly and non-selectively inhibits ionic currents in rat type I carotid body cells.
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PMID:Arachidonic acid inhibits both K+ and Ca2+ currents in isolated type I cells of the rat carotid body. 951 67


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