Skip to main content
SpringerLink
Log in

Miglustat-induced intestinal carbohydrate malabsorption is due to the inhibition of α-glucosidases, but not β-galactosidases

  • Rapid Communication
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Miglustat is an oral medication that has approved indication for type I Gaucher disease and Niemann pick disease type C. Usually treatment with Miglustat is associated with occurrence of gastrointestinal side effects similar to carbohydrate maldigestion symptoms. Here, we studied the direct influence of Miglustat on the enzymatic function of the major disaccharidases of the intestinal epithelium. Our findings show that an immediate effect of Miglustat is its interference with carbohydrate digestion in the intestinal lumen via reversible inhibition of disaccharidases that cleave α-glycosidically linked carbohydrates. Higher non physiological concentrations of Miglustat can partly affect lactase activity. We further show that the inhibition of the disaccharidases function by Miglustat is mainly competitive and does not occur via alteration of the enzyme folding.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Abbreviations

GSL:

glycosphingolipid

SI:

sucrase-isomaltase

MGA:

maltase-glucoamylase

LPH:

lactase-phlorizin hydrolase

BBM:

brush border membrane

References

  • Alfalah M, Jacob R, Preuss U, Zimmer K-P, Naim H, Naim HY (1999) O-linked glycans mediate apical sorting of human intestinal sucrase-isomaltase through association with lipid rafts. Curr Biol 9:593–596

    Article  PubMed  CAS  Google Scholar 

  • Andersson U, Butters TD, Dwek RA, Platt FM (2000) N-butyldeoxygalactonojirimycin: a more selective inhibitor of glycosphingolipid biosynthesis than N-butyldeoxynojirimycin, in vitro and in vivo. Biochem Pharmacol 59:821–829

    Article  PubMed  CAS  Google Scholar 

  • Belmatoug N, Burlina A, Giraldo P, Hendriksz CJ, Kuter DJ, Mengel E, Pastores GM (2011) Gastrointestinal disturbances and their management in miglustat-treated patients. J Inherit Metab Dis 34:991–1001

    Article  PubMed  CAS  Google Scholar 

  • Cox T, Lachmann R, Hollak C, Aerts J, van Weely S, Hrebicek M, Platt F, Butters T, Dwek R, Moyses C, Gow I, Elstein D, Zimran A (2000) Novel oral treatment of Gaucher's disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis. Lancet 355:1481–1485

    Article  PubMed  CAS  Google Scholar 

  • Elstein D, Dweck A, Attias D, Hadas-Halpern I, Zevin S, Altarescu G, Aerts J, van Weely S, Zimran A (2007) Oral maintenance clinical trial with miglustat for type I Gaucher disease: switch from or combination with intravenous enzyme replacement. Blood 110:2296–2301

    Article  PubMed  CAS  Google Scholar 

  • Hauri HP, Sterchi EE, Bienz D, Fransen JA, Marxer A (1985) Expression and intracellular transport of microvillus membrane hydrolases in human intestinal epithelial cells. J Cell Biol 101:838–851

    Article  PubMed  CAS  Google Scholar 

  • Lindner R, Naim HY (2009) Domains in biological membranes. Exp Cell Res 315:2871–2878

    Article  PubMed  CAS  Google Scholar 

  • Maiuri L, Raia V, Potter J, Swallow D, Ho MW, Fiocca R, Finzi G, Cornaggia M, Capella C, Quaroni A, Auricchio S (1991) Mosaic pattern of lactase expression by villous enterocytes in human adult-type hypolactasia. Gastroenterology 100:359–369

    PubMed  CAS  Google Scholar 

  • Naim HY, Sterchi EE, Lentze MJ (1987a) Biosynthesis and maturation of lactase phlorizin hydrolase in the human small intestinal epithelial-cells. Biochem J 241:427–434

    PubMed  CAS  Google Scholar 

  • Naim HY, Sterchi EE, Lentze MJ (1987b) Kinetics of the processing of newly synthesized sucrase-isomaltase (SI) in organ-cultures of human intestinal biopsies. Pediatr Res 22:111–111

    Article  Google Scholar 

  • Naim HY, Sterchi EE, Lentze MJ (1988) Structure, biosynthesis, and glycosylation of human small intestinal maltase-glucoamylase. J Biol Chem 263:19709–19717

    PubMed  CAS  Google Scholar 

  • Quezada-Calvillo R, Sim L, Ao Z, Hamaker BR, Quaroni A, Brayer GD, Sterchi EE, Robayo-Torres CC, Rose DR, Nichols BL (2008) Luminal starch substrate “brake” on maltase-glucoamylase activity is located within the glucoamylase subunit. J Nutr 138:685–692

    PubMed  CAS  Google Scholar 

  • Robayo-Torres CC, Quezada-Calvillo R, Nichols BL (2006) Disaccharide digestion: clinical and molecular aspects. Clin Gastroenterol Hepatol 4:276–287

    Article  PubMed  CAS  Google Scholar 

  • Rosenbaum AI, Maxfield FR (2011) Niemann-Pick type C disease: molecular mechanisms and potential therapeutic approaches. J Neurochem 116:789–795

    Article  PubMed  CAS  Google Scholar 

  • Schmitz J, Preiser H, Maestracci D, Ghosh BK, Cerda JJ, Crane RK (1973) Purification of the human intestinal brush border membrane. Biochim Biophys Acta-Biomembr 323:98–112

    Article  CAS  Google Scholar 

  • Treiber A, Morand O, Clozel M (2007) The pharmacokinetics and tissue distribution of the glucosylceramide synthase inhibitor miglustat in the rat. Xenobiotica 37:298–314

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

A Ph.D. scholarship provided by the German Academic Exchange Service (DAAD) to M.A. We thank Heshmat Akbari-Borhani for critical discussion.

Conflict of interest

This study has been supported by Actelion Pharmaceuticals GmbH.

Author information

Authors and Affiliations

  1. Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Buenteweg 17, 30559, Hannover, Germany

    Mahdi Amiri & Hassan Y. Naim

Authors
  1. Mahdi Amiri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hassan Y. Naim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hassan Y. Naim.

Additional information

Communicated by: Ed Wraith

Rights and permissions

Reprints and permissions

About this article

Cite this article

Amiri, M., Naim, H.Y. Miglustat-induced intestinal carbohydrate malabsorption is due to the inhibition of α-glucosidases, but not β-galactosidases. J Inherit Metab Dis 35, 949–954 (2012). https://doi.org/10.1007/s10545-012-9523-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10545-012-9523-9

Keywords

Search

Navigation