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

M. Reisner, S. Carmeli, M. Werman, Assaf Sukenik

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

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 μM. 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.

Original languageEnglish
Pages (from-to)620-627
Number of pages8
JournalToxicological Sciences
Volume82
Issue number2
DOIs
StatePublished - 1 Dec 2004
Externally publishedYes

Keywords

  • Cholesterol
  • Cyanobacteria
  • Cylindrospermopsin
  • Hepatotoxin
  • UMP synthase

ASJC Scopus subject areas

  • Toxicology

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