Effects of the herbicide chlorthiamid on the olfactory mucosa

Toxicology Letters
C Eriksson, E B Brittebo

Abstract

Chlorthiamid (2,6-dichlorothiobenzamide) and its major metabolite 2,6-dichlorobenzonitrile are olfactory toxicants with a high in vivo covalent binding in the olfactory mucosa of mice. This study showed that the cytochrome P450 (P450) inhibitors, metyrapone and sodium-diethyldithiocarbamate, abolished the chlorthiamid-induced toxicity (12 mg/kg; 0.06 mmol/kg) in C57B1/6 mice suggesting a P450-dependent toxicity. Incubation of [14C]-labelled chlorthiamid with rat olfactory microsomes showed a low NADPH-dependent oxidative covalent binding which was only 3-fold higher than that in liver microsomes. Thus the results do not support a major in situ metabolic activation of chlorthiamid and it is suggested that metabolic activation of the major chlorthiamid metabolite (2,6-dichlorobenzonitrile) is responsible for most of the covalent binding and toxicity of chlorthiamid at this site in vivo. Thiobenzamide (16 mg/kg; 0.12 mmol/kg), a dechlorinated chlorthiamid-analog, induced no marked morphological changes in the olfactory mucosa demonstrating that chlorines in the 2,6-position are important for the chlorthiamid-induced toxicity at this site.

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Citations

Apr 22, 2004·Gynecologic Oncology·Roberto YazigiTulio Rodriguez
Dec 31, 1997·Mutation Research·B H MathisonM S Bogdanffy
Oct 1, 1997·Toxicology in Vitro : an International Journal Published in Association with BIBRA·E B Brittebo, I Brandt
Dec 21, 2006·Toxicologic Pathology·Alan M JeffreyGary M Williams
May 6, 2009·Journal of the American Chemical Society·Tomomi AsabaNaoki Miyata

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