The cyanobacterial toxin cylindrospermopsin inhibits pyrimidine nucleotide synthesis and alters cholesterol distribution in mice

Toxicological Sciences : an Official Journal of the Society of Toxicology
M ReisnerA Sukenik

Abstract

The hepatotoxin Cylindrospermopsin, a sulfated-guanidinium alkaloid with substituted dioxypyrimidine (uracil) moiety, was isolated from several cyanobacteria species. Our previous studies on the toxicity of cylindrospermopsin and its derivatives suggested that the uracil moiety is crucial for the toxicity and that such toxicity could partly stem from competitive binding of the toxin to a catalytic site(s) involved in the synthesis of pyrimidine nucleotides (i.e., uridine). In the present study we demonstrated that cylindrospermopsin inhibited in a noncompetitive manner the in vitro activity of uridine monophosphate (UMP) synthase complex (responsible for the conversion of orotic acid to UMP) in a cell free liver extract from mice, with an inhibition constant, KI, of 10 microM. Exposure of mice to cylindrospermopsin at subacute concentrations, via drinking water, only slightly affected the in vitro activity of UMP synthase. The typical metabolic disorder associated with the inhibition of UMP synthase activity, known as "orotic aciduria," was not observed under these conditions, but other anomalous metabolic responses related to cholesterol metabolism were developed.

Citations

Jan 7, 2010·Canadian Journal of Physiology and Pharmacology·M A Labine, G Y Minuk
May 26, 2009·Toxicon : Official Journal of the International Society on Toxinology·Dániel BeyerCsaba Máthé
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Mar 21, 2021·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Leticia Díez-QuijadaÁngeles Jos

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