Inhibition by REV-5901 of leukotriene release from guinea-pig and human lung tissue in vitro

• Published in: Biochemical pharmacology Vol. 38; no. 23; p. 4183
• Main Authors: Kusner, E J, Marks, R L, Aharony, D, Krell, R D
• Format: Journal Article
• Language: English
• Published: England 01-12-1989
• Subjects: Animals; Calcimycin - pharmacology; Culture Techniques; Drug Interactions; Guinea Pigs; Histamine - metabolism; Humans; Hydroxyquinolines - pharmacology; Leukotriene B4 - analysis; Leukotriene B4 - metabolism; Lipoxygenase Inhibitors; Lung - drug effects; Lung - metabolism; Male; Prostaglandin-Endoperoxide Synthases - metabolism; Quinolines; SRS-A - metabolism; Thromboxane B2 - analysis; Time Factors
• ISSN: 0006-2952
• DOI: 10.1016/0006-2952(89)90513-3

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.