Inhibition by REV-5901 of leukotriene release from guinea-pig and human lung tissue in vitro.
The 5-lipoxygenase inhibitor REV-5901 [alpha-pentyl-3-(2-quinolinylmethoxy)benzene-methanol] was evaluated for effects on mediator release in vitro from fragmented guinea-pig and human lung. In guinea-pig lung, REV-5901 inhibited the antigen-induced release of immunoreactive leukotriene D4 (iLTD4) with an IC50 of 9.6 +/- 2.9 microM and immunoreactive leukotriene B4 (iLTB4) with an IC50 of 13.5 +/- 2.2 microM. REV-5901 also inhibited the calcium ionophore-induced release of immunoreactive leukotrienes from human lung in vitro with IC50 values of 11.7 +/- 2.2 MicroM versus peptide leukotrienes and 10.0 +/- 1.1 microM versus iLTB4. The inhibition of release of iLTD4 and iLTB4 with similar IC50 values suggests that REV-5901 acts by inhibiting 5-lipoxygenase in this system. At concentrations as high as 50 microM, REV-5901 did not inhibit the release of thromboxane B2 (TxB2), 6-keto-prostaglandin-F1 alpha (6-keto-PGF1 alpha), or histamine from either lung. The lack of effect on TxB2 and 6-keto-PGF1 alpha indicates that REV-5901 did not inhibit phospholipase A2, cyclooxygenase, or thromboxane synthetase. Inhibition of leukotriene release by REV-5901 could not be reversed by washing. Among various 5-lipoxygenase inhibitors, the order of potency for inhibition of iLTD4 release from guinea-pig lung was AA-861 greater than REV-5901 greater than phenidone greater than nafazatrom greater than NDGA greater than BW755C. These findings suggest that REV-5901 is a selective and relatively potent inhibitor of leukotriene release from lung tissue in vitro.
Kusner
E J
EJ
Department of Pharmacology, ICI Pharmaceuticals, Wilmington, DE 19897.
Marks
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Aharony
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D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D046508:Culture Techniques; D004347:Drug Interactions; D006168:Guinea Pigs; D006632:Histamine / Q000378:metabolism; D006801:Humans; D006912:Hydroxyquinolines / Q000494:pharmacology*; D007975:Leukotriene B4 / Q000032:analysis / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011804:Quinolines; D013189:SRS-A / Q000378:metabolism*; D013929:Thromboxane B2 / Q000032:analysis; D013997:Time Factors
D006912:Hydroxyquinolines; D016859:Lipoxygenase Inhibitors; D011804:Quinolines; D013189:SRS-A; C049740:alpha-pentyl-3-(2-quinolinylmethoxy)benzenemethanol; D007975:Leukotriene B4; D000001:Calcimycin; D013929:Thromboxane B2; D006632:Histamine; D011451:Prostaglandin-Endoperoxide Synthases