ToxSci Advance Access originally published online on May 5, 2004
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Toxicological Sciences 80, 3-13 (2004)
Toxicological Sciences vol. 80 no. 1 © Society of Toxicology 2004; all rights reserved.
Species and Tissue Differences in the Toxicity of 3-Butene-1,2-diol in Male Sprague-Dawley Rats and B6C3F1 Mice
* Department of Comparative Biosciences and the Molecular and Environmental Toxicology Center; and Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53706
Received February 20, 2004; accepted April 2, 2004
3-Butene-1,2-diol (BDD) is a major metabolite of 1,3-butadiene (BD), but the role of BDD in BD toxicity and carcinogenicity remains unclear. In this study, the acute toxicity of BDD was investigated in male Sprague-Dawley rats and B6C3F1 mice. Of the rats given 250 mg/kg BDD, 2 out of 4 died within 24 h; rats experienced hypoglycemia, significant alterations of liver integrity tests, and had lesions in the liver 4 h after treatment, but no lesions were detected in extrahepatic tissues. Rat hepatic GSH and GSSG levels were significantly depleted at both 1 and 4 h after the BDD treatment. Rats administered 200 mg/kg BDD also had liver lesions but no death or hypoglycemia was observed four or 24 h after treatment; these rats had depleted hepatic GSH and GSSG levels at 1 h but not at 4 or 24 h after treatment. Mice administered 250 mg/kg BDD exhibited modest alterations of liver integrity tests, but no death, hypoglycemia, or lesions in any tissue, and hepatic GSH and GSSG levels were depleted at 1 h but not at 4 h. The plasma half-life of BDD was four times longer in rats than in mice. Additional studies in rats showed the depletion of hepatic GSH and GSSG preceded the BDD-induced hypoglycemia and hepatotoxicity. Thus, the long half-life of BDD in rat plasma and the sustained depletion of hepatic GSH and GSSG may in part explain the higher sensitivity of the rat to BDD-induced hepatotoxicity. Furthermore, the results indicate that BDD may play a role in BD-induced toxicity.
Key Words: 1,3-butadiene; 3-butene-1,2-diol; rat-sensitive; hepatotoxicity; hypoglycemia; glutathione-depletion.
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