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Title: Trichothecenes induce accumulation of glucosylceramide in neural cells by interfering with lactosylceramide synthase activity

Trichothecenes are sesquiterpenoid metabolites produced by several fungal strains that impair human and animal health. Since sphingolipids were connected with fungal toxicity the aim of the present study was to test the influence of fungal metabolites on sphingolipid metabolism in neural cells. The crude extract of fungal strain Spicellum roseum induced accumulation of glucosylceramide (GlcCer), and simultaneous reduction of the formation of lactosylceramide (LacCer) and complex gangliosides in primary cultured neurons. Following a bioassay-guided fractionation of the respective fungal extract we could demonstrate that the two isolated trichothecene derivatives, 8-deoxy-trichothecin (8-dT) and trichodermol (Td-ol) were responsible for this effect. Thus, incubation of primary cultured neurons as well as of neuroblastoma B104 cells for 24 h with 30 {mu}M of either of the two fungal metabolites resulted in uncoupling of sphingolipid biosynthesis at the level of LacCer. For the observed reduction of LacCer synthase activity by about 90% cell integrity was crucial in both cell types. In neuroblastoma cells the amount of LacCer synthase mRNA was reduced in the presence of trichothecenes, whereas in primary cultured neurons this was not the case, suggesting a post-transcriptional mechanism of action in the latter cell type. The data also show that the compounds didmore » not interfere with the translocation of GlcCer in neuroblastoma cells. Collectively, our results demonstrate that trichodermol and 8-deoxy-trichothecin inhibit LacCer synthase activity in a cell-type-specific manner.« less
Authors:
 [1] ;  [2] ;  [1] ;  [3]
  1. Institute for Pharmaceutical Biology, University of Bonn (Germany)
  2. Kekule-Institute for Organic Chemistry and Biochemistry, University of Bonn (Germany)
  3. Kekule-Institute for Organic Chemistry and Biochemistry, University of Bonn (Germany), E-mail: g.echten.deckert@uni-bonn.de
Publication Date:
OSTI Identifier:
21077858
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 225; Journal Issue: 1; Other Information: DOI: 10.1016/j.taap.2007.08.005; PII: S0041-008X(07)00357-2; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANIMALS; BIOASSAY; BIOSYNTHESIS; FRACTIONATION; GANGLIOSIDES; METABOLISM; METABOLITES; NERVE CELLS; TOXICITY; TRANSLOCATION