Interactions of deoxynivalenol and lipopolysaccharides on cytotoxicity protein synthesis and metabolism of DON in porcine hepatocytes and Kupffer cell enriched hepatocyte cultures.
The cytotoxicity of deoxynivalenol (DON), effects on protein synthesis and albumin secretion was investigated in porcine hepatocytes and Kupffer cell-enriched hepatocyte cultures (co-cultures) in the presence and absence of lipopolysaccharides (LPS). Up to 16microM DON did not reduce the metabolic activity of hepatocytes. Lysosomal activity reacted more sensitively as neutral red uptake was decreased starting at 2 or 4microM DON irrespective of LPS exposure. The synthesis of secreted proteins was reduced to 31% and 42%, and of cellular proteins to 47% and 39%, in the absence and presence of LPS, respectively, when hepatocytes were exposed to 2microM DON. Reduced albumin secretion in response to DON was already observed after 3h in hepatocytes as well as co-cultures while LPS-mediated decrease was not evident until 24h, when interactions between DON and LPS resulted from a diminishing difference between LPS stimulated and non-stimulated cultures with increasing concentrations of DON. All observed effects may be biased by the cells' ability to conjugate DON to glucuronic acid as 54% and 64% of DON administered at 5nM were recovered as conjugates after 48h. Glucuronidation rate, as well as total DON recovery, decreased with increasing concentrations of DON, giving rise to assumptions on the formation of undetected metabolites.
Döll
Susanne
S
Division of Veterinary Pharmacology, Pharmacy and Toxicology, Department of Equine Science, Faculty of Veterinary Medicine, Utrecht University, The Netherlands. susanne.doell@fli.bund.de
Schrickx
Jan A
JA
Valenta
Hana
H
Dänicke
Sven
S
Fink-Gremmels
Johanna
J
D000418:Albumins / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D007150:Immunohistochemistry; D007728:Kupffer Cells / Q000187:drug effects* / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D013552:Swine; D013997:Time Factors; D014255:Trichothecenes / Q000633:toxicity*
D000418:Albumins; D008070:Lipopolysaccharides; D014255:Trichothecenes; D005978:Glutathione; C007262:deoxynivalenol