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Structure/toxicity relationships and fate of low molecular weight peptide toxins from cyanobacteria

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Title: Structure/toxicity relationships and fate of low molecular weight peptide toxins from cyanobacteria
Author(s): Dahlem, Andrew Michael
Doctoral Committee Chair(s): Beasley, Val Richard
Department / Program: Veterinary Medical Science
Discipline: Veterinary Biosciences
Degree Granting Institution: University of Illinois at Urbana-Champaign
Degree: Ph.D.
Genre: Dissertation
Subject(s): Chemistry, Pharmaceutical Biology, Veterinary Science
Abstract: Hepatic glutathione (GSH) was depleted to assess the influence of GSH on the toxicity of MCYST-LR in vivo. The GSH conjugate of MCYST-LR was also formed synthetically. There was an approximately four-fold decrease in the toxicity of the GSH derivative, as compared to the parent toxin; but the GSH conjugate remained hepatotoxic and hepatospecific in its effects.Sodium borohydride-induced structural manipulation of the dehydro amino acids of two different cyanobacterial peptides, MCYST-LR and nodularin, resulted in selectively saturated dihydro products. The dihydro products were compared with the parent toxins in toxicity trials in order to assess the role of the dehydro amino acid units in the toxicity.Tritium-labeled sodium borohydride was used to produced tritium-labeled 2H-MCYST-LR. The labeled toxin was administered intraperitoneally to male mice in lethal (200 $\mu$g/kg) or sublethal (100 $\mu$g/kg) doses, and the organ distributions measured over a 60 min observation period. Sublethal (100 $\mu$g/kg) doses were also administered to a second group of mice and the excretion of radioactivity in urine and feces was measured at 12 hr intervals for 72 hr, along with tissue distribution at the end of the observation period. Accumulation of labeled toxin in the livers of treated animals was rapid with 94.7 $\pm$ 3.3% (mean $\pm$ S.D.) of the sublethal dose present in the liver after 1 hr, and 57.8 $\pm$ 5.2% of the administered dose present 72 hr after administration. The small intestine also accumulated radioactivity in both treatment groups. Excretion of the toxin in sublethally dosed animals occurred primarily via the feces.The structure/toxicity relationships of functional substituents of microcystin-LR and nodularin were investigated. The unusual C$\sb{20}$ amino acid associated with all cyanobacterial peptide hepatotoxins described to date was synthesized its toxicity tested in vivo. Derivatives of the toxin which resulted in alteration of the ADDA substituent had reduced toxicity.
Issue Date: 1989
Type: Text
Language: English
URI: http://hdl.handle.net/2142/19868
Rights Information: Copyright 1989 Dahlem, Andrew Michael
Date Available in IDEALS: 2011-05-07
Identifier in Online Catalog: AAI8924800
OCLC Identifier: (UMI)AAI8924800
 

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