Document Detail


Cylindrospermopsin genotoxicity and cytotoxicity: role of cytochrome P-450 and oxidative stress.
MedLine Citation:
PMID:  16020200     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Cylindrospermopsin (CYN) is a cyanobacterial toxin found in drinking-water sources world wide. It was the likely cause of human poisonings in Australia and possibly Brazil. Although CYN itself is a potent protein synthesis inhibitor, its acute toxicity appears to be mediated by cytochrome p-450 (CYP450)-generated metabolites. CYN also induces genotoxic effects both in vitro and in vivo, and preliminary evidence suggests that tumors are generated by oral exposure to CYN. To understand the role of CYP450-activated CYN metabolites on in vitro genotoxicity, this study quantified the process in primary mouse hepatocytes using the COMET assay in both the presence and absence of CYP450 inhibitors known to block acute CYN cytotoxicity. CYN was cytotoxic at concentrations above 0.1 microM (EC50 = 0.5 microM) but produced significant increases in Comet tail length, area, and tail moment at 0.05 microM and above; hence genotoxicity is unlikely to be secondary to metabolic disruption due to toxicity. The CYP450 inhibitors omeprazole (100 microM) and SKF525A (50 microM) completely inhibited the genotoxicity induced by CYN. The toxin also inhibits production of glutathione (GSH), a finding confirmed in this study. This could potentiate cytotoxicity, and by implication genotoxicity, via reduced reactive oxygen species (ROS) quenching. The lipid peroxidation marker, malondialdehyde (MDA) was quantified in CYN-treated cells, and the effect of the reduced glutathione (GSSG) reductase (GSSG-rd.) inhibitor 1,3-bis(chloroethyl)-l-nitrosourea (BCNU) on both MDA production and lactate dehydrogenase (LDH) leakage was examined. MDA levels were not elevated by CYN treatment, and block of GSH regeneration by BCNU did not affect lipid peroxidation or cytotoxicity. It therefore seems likely that CYP450-derived metabolites are responsible for both the acute cytotoxicity and genotoxicity induced by CYN.
Authors:
Andrew R Humpage; Frank Fontaine; Suzanne Froscio; Philip Burcham; Ian R Falconer
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of toxicology and environmental health. Part A     Volume:  68     ISSN:  1528-7394     ISO Abbreviation:  J. Toxicol. Environ. Health Part A     Publication Date:  2005 May 
Date Detail:
Created Date:  2005-07-19     Completed Date:  2005-08-02     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  100960995     Medline TA:  J Toxicol Environ Health A     Country:  England    
Other Details:
Languages:  eng     Pagination:  739-53     Citation Subset:  IM    
Affiliation:
Department of Clinical and Experimental Pharmacology, University of Adelaide, Adelaide, Australia. andrew.humpage@sawater.com.au
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MeSH Terms
Descriptor/Qualifier:
Animals
Comet Assay
Cytochrome P-450 Enzyme System / antagonists & inhibitors,  physiology*
Hepatocytes / drug effects*,  enzymology
Lipid Peroxidation / drug effects
Male
Mice
Mutagenicity Tests
Oxidative Stress / drug effects*,  genetics
Reactive Oxygen Species / metabolism
Uracil / analogs & derivatives*,  toxicity*
Chemical
Reg. No./Substance:
0/Reactive Oxygen Species; 143545-90-8/cylindrospermopsin; 66-22-8/Uracil; 9035-51-2/Cytochrome P-450 Enzyme System

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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