Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/14418
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Type: Journal article
Title: Cylindrospermopsin-induced protein synthesis inhibition and its dissociation from acute toxicity in mouse hepatocytes
Author: Froscio, S.
Humpage, A.
Burcham, P.
Falconer, I.
Citation: Environmental Toxicology, 2003; 18(4):243-251
Publisher: John Wiley & Sons Inc
Issue Date: 2003
ISSN: 1520-4081
1522-7278
Abstract: The toxicology of the cyanobacterial alkaloid cylindrospermopsin (CYN), a potent inhibitor of protein synthesis, appears complex and is not well understood. In exposed mice the liver is the main target for the toxic effects of CYN. In this study primary mouse hepatocyte cultures were used to investigate the mechanisms involved in CYN toxicity. The results show that 1-5 microM CYN caused significant concentration-dependent cytotoxicity (52%-82% cell death) at 18 h. Protein synthesis inhibition was a sensitive, early indicator of cellular responses to CYN. Following removal of the toxin, the inhibition of protein synthesis could not be reversed, showing behavior similar to that of the irreversible inhibitor emetine. In contrast to the LDH leakage, protein synthesis was maximally inhibited by 0.5 microM CYN. No protein synthesis occurred over 4-18 h at or above this concentration. Inhibition of cytochrome P450 (CYP450) activity with 50 microM proadifen or 50 microM ketoconazole diminished the toxicity of CYN but not the effects on protein synthesis. These findings imply a dissociation of the two events and implicate the involvement of CYP450-derived metabolites in the toxicity process, but not in the impairment of protein synthesis. Thus, the total abolition of protein synthesis may exaggerate the metabolite effects but cannot be considered a primary cause of cell death in hepatocytes over an acute time frame. In cell types deficient in CYP450 enzymes, protein synthesis inhibition may play a more crucial role in the development of cytotoxicity.
Keywords: Hepatocytes; Animals; Mice; Proadifen; Uracil; Cytochrome P-450 Enzyme System; L-Lactate Dehydrogenase; DNA; Bacterial Toxins; Protein Synthesis Inhibitors; Analysis of Variance; Peptide Biosynthesis; Cytochrome P-450 Enzyme Inhibitors
RMID: 0020030486
DOI: 10.1002/tox.10121
Appears in Collections:Pharmacology publications
Environment Institute publications

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