Effects of the herbicide chlorthiamid on the olfactory mucosa.
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.
Eriksson
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Department of Pharmacology and Toxicology, Uppsala Biomedical Center, Sweden.
Brittebo
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EB
D000818:Animals; D001665:Binding Sites; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004050:Ditiocarb / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D008797:Metyrapone / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009249:NADP / Q000378:metabolism; D009570:Nitriles / Q000378:metabolism; D009831:Olfactory Mucosa / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013194:Staining and Labeling; D013854:Thioamides / Q000378:metabolism / Q000633:toxicity*; D016707:Tissue Fixation
D009570:Nitriles; D013854:Thioamides; C058670:2,6-dichlorothiobenzamide; D009249:NADP; C015539:thiobenzamide; D003577:Cytochrome P-450 Enzyme System; D004050:Ditiocarb; C055869:dichlobanil; D008797:Metyrapone