title: Extensive glycosphingolipid depletion in the liver and lymphoid organs of mice treated with N-butyldeoxynojirimycin.
abstract: The imino sugar N-butyldeoxynojirimycin is an inhibitor of the ceramide-specific glucosyltransferase that catalyzes the first step in glycosphingolipid biosynthesis. It results in extensive glycosphingolipid depletion in cells treated in vitro, without causing toxicity. However, we currently do not know the degree to which glycosphingolipids can be depleted in vivo in a mammalian species. We have therefore administered N-butyldeoxynojirimycin long term to young mice and have found that glycosphingolipid levels are reduced (50-70%) in all tissues examined, without resulting in any overt pathology. When the lymphoid tissues from these mice were examined, they were found to be 50% acellular relative to non-lymphoid tissues. These data implicate a role for glycosphingolipids in the biology of the immune system or indicate an additional as yet unknown activity of N-butyldeoxynojirimycin. Extensive glycosphingolipid depletion resulting from N-butyldeoxynojirimycin administration is therefore well tolerated in adult mice, and this compound may be in an invaluable tool for probing glycosphingolipid functions in vivo. In addition, this drug may be effective in clinical situations where glycosphingolipid depletion would be desirable, such as the in the treatment of the human glycosphingolipidoses.
authors.affiliation: Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom.
authors.forename: F M
authors.initials: FM
authors.lastname: Platt
authors.forename: G
authors.initials: G
authors.lastname: Reinkensmeier
authors.forename: R A
authors.initials: RA
authors.lastname: Dwek
authors.forename: T D
authors.initials: TD
authors.lastname: Butters
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002772:Cholera Toxin / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors*; D006028:Glycosphingolipids / Q000032:analysis*; D016130:Immunophenotyping; D008099:Liver / Q000737:chemistry / Q000187:drug effects*; D008221:Lymphoid Tissue / Q000737:chemistry / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D004791:Enzyme Inhibitors; D006028:Glycosphingolipids; D017485:1-Deoxynojirimycin; D002772:Cholera Toxin; C059896:miglustat; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase