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Chemical Compound Review

Dihydrodids     5-isothiocyanato-2-[2-(4- isothiocyanato-2...

Synonyms: Dihydro-dids, H2DIDS, H(2)DIDS, AC1L3GOE, FT-0667208, ...
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Disease relevance of H2DIDS

  • In 15 simple heterozygotes, it yielded a mild form of hereditary spherocytosis (HS) with band 3 deficiency (-20% +/- 2%) and a reduced number of 4,4'-diisothiocyano-1,2-diphenylethane-2,2'-disulfonate (H2DIDS) binding sites (-35%) [1].
  • The experiments reported in this paper were undertaken to explore the interaction of tritiated H2DIDS (4,4'-diisothiocyano-1,2,diphenyl ethane-2,2'-disulfonic acid) with Ehrlich ascites tumor cells [2].
  • Consequently, at least four modes of interaction exist between H2DIDS and ascites tumor cells [2].
  • The binding capacity of hepatocytes for H2DIDS is much higher than that of the phalloidin-insensitive hepatoma cells [3].
  • 4. Hemolysis in Tris-HCl is delayed by H2DIDS but is promoted by low concentrations of bicarbonate [4].

High impact information on H2DIDS

  • However, in contrast to the original band 3, inhibition by 4,4'-diisothiocyano dihydrostilbene-2,2'-disulfonate (H2DIDS) is no longer irreversible [5].
  • In addition, the kinetics of H2DIDS release from band 3 HT was abnormal, while the kinetics of 4,4'-dibenzamidostilbene-2,2'-disulfonate (DBDS) release showed no difference when compared with the wild-type protein [6].
  • Yet it yielded a slight decrease in band 3 (-6% to -12%) and in the number of H2DIDS binding sites (-19%) [1].
  • However, two additional heterozygotes presented with an aggravated HS and a more pronounced reduction of band 3 (-40%) and of H2DIDS binding sites (-48%) [1].
  • The band 3 protein of the red blood cell membrane catalyzes anion exchange that is inhibited by the stilbenedisulfonate derivative H2DIDS (4,4'-diisothiocyanodihydrostilbene-2,2'-disulfonic acid) [7].

Biological context of H2DIDS


Anatomical context of H2DIDS

  • Changing the Cl- gradient across the plasma membrane of acini maintained in HCO3(-)-buffered solutions reveals the presence of an H2DIDS-sensitive, Na(+)-independent, Cl(-)-dependent, HCO3- transporter with characteristics of a Cl-/HCO3- exchanger [13].
  • The transport inhibitor 4,4'-diisothiocyanatodihydrostilbene-2,2'-disulfonate (H(2)DIDS), acting from the extracellular side, blocks trypsin cleavage at K743 in unsealed membranes by inducing a protease-resistant conformation [14].
  • Our results suggest that a protein structure on the surface of hepatocytes, needed for the response to phalloidin, is influenced by DIDS or H2DIDS [3].
  • These include both reversible and irreversible binding to membrane components which regulate anion permeability, irreversible binding to cell surface proteins or glycocalyx, and finally incorporation of H2DIDS into the intracellular phase [2].
  • This paper concerns a study of the inhibition of sulfate permeability of sarcoplasmic reticulum vesicles by stilbene derivatives, such as 4-acetoamido-4'-isothiocyano-2,2'-stilbene-disulfonic acid (SITS), 4,4'-diisothiocyano-stilbene-2,2'-disulfonic acid (DIDS), and diisothiocyano-1,2-diphenyl-ethane-2,2'-disulfonic acid (H2DIDS) [15].

Associations of H2DIDS with other chemical compounds

  • The anion transport inhibitor H2DIDS (4,4'-diisothiocyanodihydrostilbene-2,2'-disulfonate) reacts covalently with a lysine residue on P28, rather than P7, in native band 3 [16].
  • Transmembrane effects of intracellular chloride on the inhibitory potency of extracellular H2DIDS. Evidence for two conformations of the transport site of the human erythrocyte anion exchange protein [17].
  • SP did not inhibit secretion further when H(2)DIDS was present in the lumen, suggesting that SP and H(2)DIDS both inhibit the activity of an anion exchanger on the luminal membrane of the duct cell [18].
  • Experiments were performed in the absence of sodium; the presence of 2.5 mM amiloride, a potent inhibitor of the Na(+)/H(+) antiport; in the absence of bicarbonate; and in the presence of 4, 4'-diisothiocyanatodihydrostilbene-2,2'-di-sulfonic acid, disodium salt (H(2)DIDS) for all three activation methods [19].
  • In response to sudden acidification or alkalization of the ASL by approximately 0.4 pH units by HCl/NaOH, ASL pH recovered to its initial value at a rate of 0.035 pH units/min (-HCO) and 0.060 pH units/min (+HCO); the pH recovery rate was reduced by amiloride and H(2)DIDS [20].

Gene context of H2DIDS

  • Recovery from this alkaline shift was dependent on mucosal Cl-, was insensitive to the AE inhibitor 4,4'-diisothiocyanatodihydrostilbene-2,2'-disulfonic acid (H2DIDS; 1.5 mM), but was sensitive to the cystic fibrosis transmembrane conductance regulator (CFTR) channel inhibitor diphenylamine-2-carboxylate (DPC; 100 microM) [21].
  • Measurements of 36Cl- efflux indicate that the translation product mediates Cl- transport, which is inhibitable reversibly by DNDS or H2DIDS, specific inhibitors of band 3-mediated transport [22].
  • In explants cultured in the presence of H2DIDS, expression of NCAM and the anterior neural gene otx2 is greatly reduced or absent [10].
  • The effect of mutation of either Lys 558 or Lys 869 or both on mouse erythroid band 3 protein (AE1)-mediated 36Cl- efflux and its inhibition by pyridoxal 5-phosphate (P5-P), DNDS and H2DIDS were studied [23].
  • Mutation of Lys 558 (K558N), the site of covalent binding of H2DIDS (4,4'-diisothiocyanostilbene-2,2'-disulfonate) in the outer membrane surface, in combination with any one of the His/Gln mutations leads to partial (H721Q; H837Q) or complete (H852Q) restoration of Cl- flux [24].

Analytical, diagnostic and therapeutic context of H2DIDS

  • After treatment with the impermeant anion transport blocker DIDS, or in the presence of the reduced analog H2DIDS, pHi decreased by > or = 0.2 unit [25].
  • The profile of radioactivity, following trypsinolysis and SDS-PAGE, showed H2DIDS attachment to a 52-kDa fragment which also contains the ATP binding site [26].
  • Deglycosylation of band 3 or proteolytic cleavage of the extramembranous loops did not enhance immunoprecipitation of H2DIDS-labelled band 3 [27].
  • Circular dichroism (CD) measurements of this H2DIDS-labelled complex showed that it had a very high helical content (86%) [27].
  • Peritubular perfusion with 300 microM 4,4'-diisothiocanatodihydrostilbene-2,2'-disulphonic acid (H2DIDS) caused an intracellular alkalinisation [28].


  1. Modulation of clinical expression and band 3 deficiency in hereditary spherocytosis. Alloisio, N., Texier, P., Vallier, A., Ribeiro, M.L., Morlé, L., Bozon, M., Bursaux, E., Maillet, P., Gonçalves, P., Tanner, M.J., Tamagnini, G., Delaunay, J. Blood (1997) [Pubmed]
  2. Interaction of tritium-labeled H2DIDS (4,4'-diisothiocyano-1,2,diphenyl ethane-2,2'disulfonic acid) with the Ehrlich mouse ascites tumor cell. Levinson, C., Corcoran, R.J., Edwards, E.H. J. Membr. Biol. (1979) [Pubmed]
  3. Inhibitory effects of 4,4'-diisothiocyano stilbene-2,2'-disulfonic acid (DIDS) in the response of isolated hepatocytes to phalloidin. Petzinger, E., Grundmann, E., Veil, L.B., Frimmer, M., Fasold, H. Naunyn Schmiedebergs Arch. Pharmacol. (1978) [Pubmed]
  4. Transfer of Tris buffer and effects on K+ loss in human red blood cells and reconstituted ghosts. Bodemann, H.H., Karsch, B. Biochim. Biophys. Acta (1984) [Pubmed]
  5. Anion transport in oocytes of Xenopus laevis induced by expression of mouse erythroid band 3 protein--encoding cRNA and of a cRNA derivative obtained by site-directed mutagenesis at the stilbene disulfonate binding site. Bartel, D., Lepke, S., Layh-Schmitt, G., Legrum, B., Passow, H. EMBO J. (1989) [Pubmed]
  6. Differential sensitivity of stilbenedisulfonates in their reaction with band 3 HT (Pro-868-->Leu). Salhany, J.M., Schopfer, L.M., Kay, M.M., Gamble, D.N., Lawrence, C. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  7. Red blood cell band 3. Lysine 539 and lysine 851 react with the same H2DIDS (4,4'-diisothiocyanodihydrostilbene-2,2'-disulfonic acid) molecule. Okubo, K., Kang, D., Hamasaki, N., Jennings, M.L. J. Biol. Chem. (1994) [Pubmed]
  8. Reductive methylation of the two 4,4'-diisothiocyanodihydrostilbene-2,2'-disulfonate-binding lysine residues of band 3, the human erythrocyte anion transport protein. Jennings, M.L. J. Biol. Chem. (1982) [Pubmed]
  9. Cytosolic pH regulation in osteoblasts. Regulation of anion exchange by intracellular pH and Ca2+ ions. Green, J., Yamaguchi, D.T., Kleeman, C.R., Muallem, S. J. Gen. Physiol. (1990) [Pubmed]
  10. The role of intracellular alkalinization in the establishment of anterior neural fate in Xenopus. Uzman, J.A., Patil, S., Uzgare, A.R., Sater, A.K. Dev. Biol. (1998) [Pubmed]
  11. Fluid secretion in interlobular ducts isolated from guinea-pig pancreas. Ishiguro, H., Naruse, S., Steward, M.C., Kitagawa, M., Ko, S.B., Hayakawa, T., Case, R.M. J. Physiol. (Lond.) (1998) [Pubmed]
  12. Multiple transport functions of a red blood cell anion exchanger, tAE1: its role in cell volume regulation. Guizouarn, H., Gabillat, N., Motais, R., Borgese, F. J. Physiol. (Lond.) (2001) [Pubmed]
  13. Intracellular pH-regulatory mechanisms in pancreatic acinar cells. I. Characterization of H+ and HCO3- transporters. Muallem, S., Loessberg, P.A. J. Biol. Chem. (1990) [Pubmed]
  14. Topology of the anion exchange protein AE1: the controversial sidedness of lysine 743. Kuma, H., Shinde, A.A., Howren, T.R., Jennings, M.L. Biochemistry (2002) [Pubmed]
  15. Inhibition of the anion permeability of sarcoplasmic reticulum vesicles by some stilbene derivatives. Kasai, M. J. Biochem. (1981) [Pubmed]
  16. Peptides of human erythrocyte band 3 protein produced by extracellular papain cleavage. Jennings, M.L., Adams-Lackey, M., Denney, G.H. J. Biol. Chem. (1984) [Pubmed]
  17. Transmembrane effects of intracellular chloride on the inhibitory potency of extracellular H2DIDS. Evidence for two conformations of the transport site of the human erythrocyte anion exchange protein. Furuya, W., Tarshis, T., Law, F.Y., Knauf, P.A. J. Gen. Physiol. (1984) [Pubmed]
  18. Protein kinase C mediates the inhibitory effect of substance P on HCO3- secretion from guinea pig pancreatic ducts. Hegyi, P., Rakonczay, Z., Tiszlavicz, L., Varró, A., Tóth, A., Rácz, G., Varga, G., Gray, M.A., Argent, B.E. Am. J. Physiol., Cell Physiol. (2005) [Pubmed]
  19. Mechanism of intracellular pH increase during parthenogenetic activation of In vitro matured porcine oocytes. Ruddock, N.T., Macháty, Z., Milanick, M., Prather, R.S. Biol. Reprod. (2000) [Pubmed]
  20. Airway surface liquid pH in well-differentiated airway epithelial cell cultures and mouse trachea. Jayaraman, S., Song, Y., Verkman, A.S. Am. J. Physiol., Cell Physiol. (2001) [Pubmed]
  21. Polarized distribution of HCO3- transport in human normal and cystic fibrosis nasal epithelia. Paradiso, A.M., Coakley, R.D., Boucher, R.C. J. Physiol. (Lond.) (2003) [Pubmed]
  22. Mediation of inorganic anion transport by the hydrophobic domain of mouse erythroid band 3 protein expressed in oocytes of Xenopus laevis. Lepke, S., Becker, A., Passow, H. Biochim. Biophys. Acta (1992) [Pubmed]
  23. Role of Lys 558 and Lys 869 in substrate and inhibitor binding to the murine band 3 protein: a study of the effects of site-directed mutagenesis of the band 3 protein expressed in the oocytes of Xenopus laevis. Wood, P.G., Müller, H., Sovak, M., Passow, H. J. Membr. Biol. (1992) [Pubmed]
  24. Inhibition of mouse erythroid band 3-mediated chloride transport by site-directed mutagenesis of histidine residues and its reversal by second site mutation of Lys 558, the locus of covalent H2DIDS binding. Müller-Berger, S., Karbach, D., König, J., Lepke, S., Wood, P.G., Appelhans, H., Passow, H. Biochemistry (1995) [Pubmed]
  25. The role of anions in pH regulation of Leishmania major promastigotes. Vieira, L., Lavan, A., Dagger, F., Cabantchik, Z.I. J. Biol. Chem. (1994) [Pubmed]
  26. Inhibition and derivatization of the renal Na,K-ATPase by dihydro-4,4'-diisothiocyanatostilbene-2,2'-disulfonate. Pedemonte, C.H., Kaplan, J.H. Biochemistry (1988) [Pubmed]
  27. Transmembrane helix-helix interactions and accessibility of H2DIDS on labelled band 3, the erythrocyte anion exchange protein. Landolt-Marticorena, C., Casey, J.R., Reithmeier, R.A. Mol. Membr. Biol. (1995) [Pubmed]
  28. Intracellular pH in renal tubules in situ: single-cell measurements by confocal laserscan microscopy. Weinlich, M., Capasso, G., Kinne, R.K. Pflugers Arch. (1993) [Pubmed]
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