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Chemical Compound Review

VERLUKAST     3-[[3-[(E)-2-(7- chloroquinolin-2...

Synonyms: CHEMBL15177, MK-571, MK-0571, MK-0679, CHEBI:115282, ...
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Disease relevance of MK 679


High impact information on MK 679

  • Treatment with MK-571 attenuated exercise-induced bronchoconstriction in all the subjects [6].
  • In 3 Pgp-positive/MRP-positive samples, MK-571 enhanced GO-induced cytotoxicity in the presence of CSA [7].
  • MK-571 enhanced GO-induced cytotoxicity in Pgp-negative/MRP-positive NB4 and HL-60 cells [7].
  • LTD4-induced calcium fluxes were also observed in granulocytes but were not reduced by MK-571, suggesting that these effects were mediated by other receptors (eg, CysLT2) rather than by CysLT1 [8].
  • A variability in MRP activity, expressed as CF efflux-blocking by MK-571, was observed (efflux-blocking factors varied between 1.2 and 3.6); this correlated with the number of MRP1 genes (r = 0.91, P <. 01) [9].

Chemical compound and disease context of MK 679


Biological context of MK 679

  • Interleukin-6 production by activated human monocytic cells is enhanced by MK-571, a specific inhibitor of the multi-drug resistance protein-1 [13].
  • ICI-204,219 was 5 to 10 times more potent than MK-0571 (IC50 values of 1.1 and 9.3 nM, respectively), in agreement with results from radioligand binding studies reported separately [14].
  • On the other hand, the leukotriene (LT) B(4) receptor antagonist U-75302, the LTD(4) receptor antagonists LY-171883 and MK-571, and the cysteinyl-LT receptor antagonist REV-5901 also inhibit cell proliferation and [(3)H]-thymidine incorporation in a concentration-dependent manner, and delay the RAW 264.7 cell cycle [15].
  • Bioavailabilities of the S-(+)- and R-(-)-enantiomers in the rat were similar (75% and 71%, respectively) suggesting that MK-571 was not stereoselectively absorbed in that species [16].
  • The results of this study suggest that inhalation of MK-679 should be a considered route of administration for the treatment of asthma [17].

Anatomical context of MK 679

  • The enhancement was not prevented by CysLT1R antagonists (MK-571 and montelukast) or by a dual antagonist (BAY u9773), which is consistent with the lack of detectable mRNA for CysLT1R and CysLT2R in bronchial fibroblasts [18].
  • Saquinavir efflux was directional, not saturable, and was inhibited by MK-571 (35 and 75 micro M) in all cell lines [19].
  • In addition, MK-571 (1 mg/kg/day) given for at least 1 day after injury in a model of balloon catheter injury of rat carotid artery, provided effective inhibition of myointimal VSMC proliferation, with a 58% reduction of 5-bromo-2'-deoxyuridine (BrdU) uptake in the neointima and 69% reduction of neointimal thickening [20].
  • ATP release from astrocytes in HOS was observed directly using luciferin-luciferase and MK-571 reversibly depressed this HOS-induced ATP efflux [21].
  • Since LTs play a major role in control of cytokine expression in monocytes, we questioned whether blocking of the MRPI mediated function by MK-571 might affect cytokine production [13].

Associations of MK 679 with other chemical compounds

  • ATP-dependent LTC4 transport was effectively inhibited by the LTD4 receptor antagonist MK 571, whereas cyclosporin A and, particularly, its analog PSC 833 were much less potent [22].
  • The effect of specific inhibitors of P-gp (GF 120918) and MRP1 (MK 571) was also examined [23].
  • The ET-1 effects were not influenced by pretreatment with either the cyclo-oxygenase inhibitor indomethacin or the leukotriene receptor antagonist MK-571, indicating that ET-1-induced depression in TMV does not involve the activation of prostanoids or peptide leukotrienes [24].
  • The functional activity of P-gp and MRP, expressed as Rh123 efflux blocking by PSC833 and CF efflux blocking by MK-571, demonstrated a great variability in the AML patients [25].
  • Airways mucus after recombinant murine IL-13-challenge was reduced by zileuton and by LY171883, MK-571, and PH-163 [26].

Gene context of MK 679

  • P-gp and MRP activity varied strongly between the cases (rhodamine 123 efflux-blocking by PSC833: 5.4+/-7.7, and carboxyfluorescein efflux-blocking by MK-571: 4.3+/-6.7, n = 60) [27].
  • Using inside-out vesicles prepared from human erythrocytes we have shown that mefloquine and MK-571 inhibit transport of 3 microM [(3)H]DNP-SG known to be mediated by MRP1 (IC(50) 127 and 1.1 microM, respectively) and of 3.3 microM [(3)H]cGMP thought but not proven to be mediated primarily by MRP4 (IC(50) 21 and 0.41 microM) [28].
  • The rank order of inhibitory potency of MK-571 was determined as OATP1B1 (IC50: 0.3 microM) > MRP2 (4 microM) > P-gp (25 microM) [29].
  • Blocking Mrp activity by MK-571 resulted in accumulation of the Mrp specific substrate carboxyfluorescein in RLF phi 13 cells [30].
  • Finally it was shown that the MK-571 mediated effects on IL-6 secretion could not be inhibited by the LT synthesis inhibitor SB203347 or by the anti-oxidant pyrrolidine dithiocarbamate (PDTC) [13].

Analytical, diagnostic and therapeutic context of MK 679


  1. Opposing and hierarchical roles of leukotrienes in local innate immune versus vascular responses in a model of sepsis. Benjamim, C.F., Canetti, C., Cunha, F.Q., Kunkel, S.L., Peters-Golden, M. J. Immunol. (2005) [Pubmed]
  2. Toxicity of human monocytic THP-1 cells and microglia toward SH-SY5Y neuroblastoma cells is reduced by inhibitors of 5-lipoxygenase and its activating protein FLAP. Klegeris, A., McGeer, P.L. J. Leukoc. Biol. (2003) [Pubmed]
  3. The leukotriene-receptor antagonist MK-0679 blocks airway obstruction induced by inhaled lysine-aspirin in aspirin-sensitive asthmatics. Dahlén, B., Kumlin, M., Margolskee, D.J., Larsson, C., Blomqvist, H., Williams, V.C., Zetterström, O., Dahlén, S.E. Eur. Respir. J. (1993) [Pubmed]
  4. Involvement of LTD(4)in allergic pulmonary inflammation in mice: modulation by cysLT(1)antagonist MK-571. Blain, J.F., Sirois, P. Prostaglandins Leukot. Essent. Fatty Acids (2000) [Pubmed]
  5. Synergistic antiallergic activity of combined histamine H1- and cysteinyl leukotriene1-receptor blockade in human bronchus. Ruck, L.M., Rizzo, C.A., Anthes, J.C., Eckel, S., Egan, R.W., Cuss, F.M., Hey, J.A. Life Sci. (2001) [Pubmed]
  6. Inhibition of exercise-induced bronchoconstriction by MK-571, a potent leukotriene D4-receptor antagonist. Manning, P.J., Watson, R.M., Margolskee, D.J., Williams, V.C., Schwartz, J.I., O'Byrne, P.M. N. Engl. J. Med. (1990) [Pubmed]
  7. Multidrug resistance protein attenuates gemtuzumab ozogamicin-induced cytotoxicity in acute myeloid leukemia cells. Walter, R.B., Raden, B.W., Hong, T.C., Flowers, D.A., Bernstein, I.D., Linenberger, M.L. Blood (2003) [Pubmed]
  8. Chemotaxis and transendothelial migration of CD34(+) hematopoietic progenitor cells induced by the inflammatory mediator leukotriene D4 are mediated by the 7-transmembrane receptor CysLT1. Bautz, F., Denzlinger, C., Kanz, L., Möhle, R. Blood (2001) [Pubmed]
  9. Deletion of the multidrug resistance protein MRP1 gene in acute myeloid leukemia: the impact on MRP activity. van Der Kolk, D.M., Vellenga, E., van Der Veen, A.Y., Noordhoek, L., Timmer-Bosscha, H., Ossenkoppele, G.J., Raymakers, R.A., Müller, M., van Den Berg, E., de Vries, E.G. Blood (2000) [Pubmed]
  10. Nonsteroidal anti-inflammatory drugs potentiate 1-methyl-4-phenylpyridinium (MPP+)-induced cell death by promoting the intracellular accumulation of MPP+ in PC12 cells. Morioka, N., Kumagai, K., Morita, K., Kitayama, S., Dohi, T. J. Pharmacol. Exp. Ther. (2004) [Pubmed]
  11. Immediate hypersensitivity reactions in the guinea-pig conjunctiva: studies with a second-generation leukotriene D4 receptor antagonist, MK-571. Chan, C.C., Dagenais, F., Firby, P., Foster, A., Ford-Hutchinson, A.W. Can. J. Physiol. Pharmacol. (1989) [Pubmed]
  12. Bronchodilation with a potent and selective leukotriene D4 (LTD4) receptor antagonist (MK-571) in patients with asthma. Gaddy, J.N., Margolskee, D.J., Bush, R.K., Williams, V.C., Busse, W.W. Am. Rev. Respir. Dis. (1992) [Pubmed]
  13. Interleukin-6 production by activated human monocytic cells is enhanced by MK-571, a specific inhibitor of the multi-drug resistance protein-1. Vellenga, E., Tuyt, L., Wierenga, B.J., Müller, M., Dokter, W. Br. J. Pharmacol. (1999) [Pubmed]
  14. Leukotriene D4-induced increases in cytosolic calcium in THP-1 cells: dependence on extracellular calcium and inhibition with selective leukotriene D4 receptor antagonists. Chan, C.C., Ecclestone, P., Nicholson, D.W., Metters, K.M., Pon, D.J., Rodger, I.W. J. Pharmacol. Exp. Ther. (1994) [Pubmed]
  15. Role of 5-lipoxygenase pathway in the regulation of RAW 264.7 macrophage proliferation. Nieves, D., Moreno, J.J. Biochem. Pharmacol. (2006) [Pubmed]
  16. Interspecies differences in stereoselective protein binding and clearance of MK-571. Tocco, D.J., deLuna, F.A., Duncan, A.E., Hsieh, J.H., Lin, J.H. Drug Metab. Dispos. (1990) [Pubmed]
  17. Physiological disposition of aerosolized MK-679 in rats. Tocco, D.J., deluna, F.A., Vadas, E., Lin, J.H. Drug Metab. Dispos. (1992) [Pubmed]
  18. Cysteinyl leukotrienes synergize with growth factors to induce proliferation of human bronchial fibroblasts. Yoshisue, H., Kirkham-Brown, J., Healy, E., Holgate, S.T., Sampson, A.P., Davies, D.E. J. Allergy Clin. Immunol. (2007) [Pubmed]
  19. Direct evidence that saquinavir is transported by multidrug resistance-associated protein (MRP1) and canalicular multispecific organic anion transporter (MRP2). Williams, G.C., Liu, A., Knipp, G., Sinko, P.J. Antimicrob. Agents Chemother. (2002) [Pubmed]
  20. Cysteinyl leukotriene D4 induced vascular smooth muscle cell proliferation: a possible role in myointimal hyperplasia. Porreca, E., Di Febbo, C., Di Sciullo, A., Angelucci, D., Nasuti, M., Vitullo, P., Reale, M., Conti, P., Cuccurullo, F., Poggi, A. Thromb. Haemost. (1996) [Pubmed]
  21. ATP released from astrocytes during swelling activates chloride channels. Darby, M., Kuzmiski, J.B., Panenka, W., Feighan, D., MacVicar, B.A. J. Neurophysiol. (2003) [Pubmed]
  22. The MRP gene encodes an ATP-dependent export pump for leukotriene C4 and structurally related conjugates. Leier, I., Jedlitschky, G., Buchholz, U., Cole, S.P., Deeley, R.G., Keppler, D. J. Biol. Chem. (1994) [Pubmed]
  23. P-Glycoprotein and transporter MRP1 reduce HIV protease inhibitor uptake in CD4 cells: potential for accelerated viral drug resistance? Jones, K., Bray, P.G., Khoo, S.H., Davey, R.A., Meaden, E.R., Ward, S.A., Back, D.J. AIDS (2001) [Pubmed]
  24. Endothelin-1 depresses tracheal mucus velocity in ovine airways via ET-A receptors. Sabater, J.R., Otero, R., Abraham, W.M., Wanner, A., O'Riordan, T.G. Am. J. Respir. Crit. Care Med. (1996) [Pubmed]
  25. P-glycoprotein and multidrug resistance protein activities in relation to treatment outcome in acute myeloid leukemia. van der Kolk, D.M., de Vries, E.G., van Putten, W.J., Verdonck, L.F., Ossenkoppele, G.J., Verhoef, G.E., Vellenga, E. Clin. Cancer Res. (2000) [Pubmed]
  26. Leukotrienes mediate murine bronchopulmonary hyperreactivity, inflammation, and part of mucosal metaplasia and tissue injury induced by recombinant murine interleukin-13. Vargaftig, B.B., Singer, M. Am. J. Respir. Cell Mol. Biol. (2003) [Pubmed]
  27. Activity and expression of the multidrug resistance proteins P-glycoprotein, MRP1, MRP2, MRP3 and MRP5 in de novo and relapsed acute myeloid leukemia. van der Kolk, D.M., de Vries, E.G., Noordhoek, L., van den Berg, E., van der Pol, M.A., Müller, M., Vellenga, E. Leukemia (2001) [Pubmed]
  28. Interactions of mefloquine with ABC proteins, MRP1 (ABCC1) and MRP4 (ABCC4) that are present in human red cell membranes. Wu, C.P., Klokouzas, A., Hladky, S.B., Ambudkar, S.V., Barrand, M.A. Biochem. Pharmacol. (2005) [Pubmed]
  29. Effects of fibrates on human organic anion-transporting polypeptide 1B1-, multidrug resistance protein 2- and P-glycoprotein-mediated transport. Yamazaki, M., Li, B., Louie, S.W., Pudvah, N.T., Stocco, R., Wong, W., Abramovitz, M., Demartis, A., Laufer, R., Hochman, J.H., Prueksaritanont, T., Lin, J.H. Xenobiotica (2005) [Pubmed]
  30. ATP binding cassette transporter gene expression in rat liver progenitor cells. Ros, J.E., Roskams, T.A., Geuken, M., Havinga, R., Splinter, P.L., Petersen, B.E., LaRusso, N.F., van der Kolk, D.M., Kuipers, F., Faber, K.N., Müller, M., Jansen, P.L. Gut (2003) [Pubmed]
  31. Roles of calcitonin gene-related peptide (CGRP) in hyperpnea-induced constriction in guinea pigs. Nagase, T., Ohga, E., Katayama, H., Sudo, E., Aoki, T., Matsuse, T., Ouchi, Y., Fukuchi, Y. Am. J. Respir. Crit. Care Med. (1996) [Pubmed]
  32. Effect of the leukotriene receptor antagonist MK-0679 on baseline pulmonary function in aspirin sensitive asthmatic subjects. Dahlén, B., Margolskee, D.J., Zetterström, O., Dahlén, S.E. Thorax (1993) [Pubmed]
  33. Cellular uptake and efflux of the tea flavonoid (-)epicatechin-3-gallate in the human intestinal cell line Caco-2. Vaidyanathan, J.B., Walle, T. J. Pharmacol. Exp. Ther. (2003) [Pubmed]
  34. Human T cell cytokine responses are dependent on multidrug resistance protein-1. Zhang, J., Alston, M.A., Huang, H., Rabin, R.L. Int. Immunol. (2006) [Pubmed]
  35. Separation of late bronchial responses from airway hyperresponsiveness in allergic sheep. Solér, M., Sielczak, M., Abraham, W.M. J. Appl. Physiol. (1991) [Pubmed]
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