Structural requirements for chemotactic activity of leukotriene B4 (LTB4)

Hoffstein, S.T.; Manzi, R.M.; Razgaitis, K. A.; Bender, Paul E.; Gleason, John G.

doi:10.1016/0090-6980(86)90047-x

Cited by 20 publications

(3 citation statements)

References 13 publications

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“…This is supported by the fact that ebselen is inactive against carrageenan-induced pleuritis in rats (unpublished results), while NSAIDs are potent inhibitors of exudation and leucocyte recruitment in this model [20]. In view of its ability to inhibit 5-!ipoxygenase and to isomerise LTB 4 to the biologically inactive [21] transisomer [8,22], as well as inactivating inorganic and organic hydroperoxides [5,6] and inhibiting leucocyte NADPH oxidase [9,10], any or all of these actions may be responsible for the oedemainhibiting properties of ebselen in rive. CVF-induced rat paw oedema has been shown previously to be differentially sensitive to inhibitors compared to the carrageenan model [17].…”

Section: Discussionmentioning

confidence: 77%

Acute antiinflammatory and gastric effects of the seleno-organic compound ebselen

Leyck¹,

Parnham²

1990

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Ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one), a seleno-organic compound with glutathione peroxidase-like activity in vitro, was compared with indomethacin, BW 755C, and levamisole as an inhibitor of carrageenan- and CVF (cobra venom factor)-induced paw oedema in the rat. The antiinflammatory potency of ebselen against CVF-induced oedema (ED50 = 56 mg/kg p.o.) was similar to that of BW 755C, while indomethacin was weakly active in this model, and levamisole exerted stronger activity. In the carrageenan model, ebselen exhibited weak inhibitory potency, like BW 755C, while indomethacin markedly inhibited this inflammatory response, and levamisole was inactive. Unlike cyclooxygenase inhibitors, ebselen produced almost no gastric irritation in rats up to 316 mg/kg p.o. Moreover, ebselen inhibited significantly diclofenac-induced gastric intolerance at 31.6 and 316 mg/kg p.o. Thus, ebselen represents a new tool for antiinflammatory therapy.

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Section: Discussionmentioning

confidence: 77%

Acute antiinflammatory and gastric effects of the seleno-organic compound ebselen

Leyck¹,

Parnham²

1990

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“…Thus these results suggest that, although the binding affinity of LTB4 to the receptor may be high (0.18 nM) or low (0.52-0.55 nM), the specificity of the receptors both in the high-and the low-affinity state appears to be identical. Frame-shift of agonist binding affinity constants According to the proposed molecular model [16], LTB4 [5,8], guinea pig spleen membranes [13] and human lung membranes (B. Votta & S. Mong unpublished work), and those determined from the human and rabbit PMN chemotaxis studies [2,3,6,7,[10][11][12]. Thus .…”

Section: Reagentsmentioning

confidence: 99%

Transition of affinity states for leukotriene B4 receptors in sheep lung membranes

Votta¹,

Mong²

1990

Biochemical Journal

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Leukotriene B4 (LTB4) is a pro-inflammatory arachidonate metabolite. We have characterized the LTB4 receptors in sheep lung membranes and have assessed the contribution of the guanine-nucleotide-binding (G) In competition experiments, the rank order of affinity of LTB4 analogues was LTB4 > 20-OH-LTB4 > trans-homo-LTB4> 6-trans-LTB4 > 20-COOH-LTB4, using either untreated or alkali-treated membranes, both in the presence and absence of GTP [S]. These findings demonstrate that, in sheep lung membranes, there is only one class of LTB4 receptor. Removal of the Gprotein or uncoupling of the receptor from the G-protein shifted the agonist-binding affinity of the receptor by 3-4-fold, without affecting the specificity of the LTB4 receptor in either the high-or the low-affinity state.

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“…LTB4 elicits these responses by activation of an inhibitory guanine-nucleotidebinding protein (G1)-coupled membrane receptor [3][4][5][6][7][8]. Radio-ligand binding studies and functional studies have demonstrated that the G,-protein-coupled receptor binds [3H]LTB4 with high affinity [9][10][11][12] and the Gi-protein-uncoupled receptor binds [3H]LTB4 with low affinity [1,[13][14][15]. A molecular model of receptor-Gi-protein interaction was proposed [7] to account for the mechanism of high-affinity state to low-affinity state transition for the ligand receptor binding.…”

Section: Introductionmentioning

confidence: 99%

Characterization of the soluble leukotriene B4 receptor from sheep lung membranes

Votta

Keefer

Mong

1990

Biochemical Journal

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Leukotriene B4 (LTB4) is an arachidonate metabolite which elicits a variety of pro-inflammatory responses by activation of a guanine-nucleotide-binding protein-coupled membrane receptor. As a prelude to receptor isolation and purification, we have established assay methods for LTB4 receptor solubilization and characterization from sheep lung membranes.[3H]LTB4 binding to the soluble receptor was saturable, specific, protein-concentration-and time-dependent and reversible. Binding of [3H]LTB4 was enhanced by divalent cations and inhibited by sodium ions in a manner analogous to its binding to the human leukocyte membrane receptor. Saturation binding yielded a dissociation constant (Kd) of 0.50 + 0.05 nm and a receptor density (Bmax ) of 330 + 90 fmol/mg of protein for [3H]LTB4 binding to detergent-solubilized receptor. In competition experiments, the rank order of binding affinity was LTB4 > 20-OH-LTB4 > trans-homo-LTB4 > 6-trans-LTB4 > U-75302. Gel-filtration chromatography showed that the LTB4 receptor protein in the detergent micellar state has a molecular mass in the range 800-1000 kDa. These results demonstrate that the physiologically and pharmacologically important LTB4 receptor may be readily solubilized from sheep lung membranes without alteration in binding specificity and characteristics, suggesting that sheep lung membranes represent a rich source with which to pursue receptor isolation and purification.

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Structural requirements for chemotactic activity of leukotriene B4 (LTB4)

Cited by 20 publications

References 13 publications

Acute antiinflammatory and gastric effects of the seleno-organic compound ebselen

Acute antiinflammatory and gastric effects of the seleno-organic compound ebselen

Transition of affinity states for leukotriene B4 receptors in sheep lung membranes

Characterization of the soluble leukotriene B4 receptor from sheep lung membranes

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