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ToxSci Advance Access originally published online on September 1, 2004
Toxicological Sciences 2004 82(2):620-627; doi:10.1093/toxsci/kfh267
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Toxicological Sciences vol. 82 no. 2 © Society of Toxicology 2004; all rights reserved.

The Cyanobacterial Toxin Cylindrospermopsin Inhibits Pyrimidine Nucleotide Synthesis and Alters Cholesterol Distribution in Mice

M. Reisner*, S. Carmeli{dagger}, M. Werman{ddagger} and A. Sukenik§,1

* Department of Food Engineering and Biotechnology, Technion, Israel Institute of Technology, Haifa 32000 Israel; {dagger} School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel; {ddagger} Ministry of Health, District Health Office, Public Health Laboratory, P.O. Box 9526, Haifa, 35055, Israel; and § Israel Oceanographic and Limnological Research, Yigal Allon Kinneret Limnological Laboratory, P.O. Box 447, Migdal Gigdal 14950, Israel

Received April 29, 2004; accepted July 12, 2004

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.

Key Words: hepatotoxin; cyanobacteria; cylindrospermopsin; UMP synthase; cholesterol.


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