Olfactory toxicity of diethyldithiocarbamate (DDTC) and disulfiram and the protective effect of DDTC against the olfactory toxicity of dichlobenil.
Disulfiram and its breakdown product diethyldithiocarbamate (DDTC) have been investigated for their potential to protect against chemically-induced toxicity and carcinogenesis because of their inhibitory effects on cytochrome P450 2E1. We used DDTC in order to examine the role that cytochrome P450 2E1 plays in the bioactivation of beta,beta'-iminodipropionitrile (IDPN) and 2,6-dichlorobenzonitrile (dichlobenil), resulting in site-specific olfactory lesions in the Long-Evans rat and C57B1 mouse. DDTC and disulfiram themselves produced olfactory mucosal lesions in the rat, whereas DDTC protected against the olfactory toxic effects of dichlobenil in the mouse. A dose-response study revealed that approximately twice the dose of DDTC was required in mice to cause the same olfactory toxic effects seen in the rat. A study to determine the catalytic activity of P450 2E1 by p-nitrophenol (PNP) hydroxylation indicated that the Long-Evans rat nasal mucosa is 2.4 times more active than the C57B1 mouse, which may account for the greater susceptibility of the rat to the olfactory toxic effects of DDTC. PNP hydroxylation assays confirmed that DDTC decreased P450 2E1 activity in both the rat and mouse liver and nasal mucosa. Whereas the results of the mouse study strengthen the hypothesis that dichlobenil is bioactivated to a toxic metabolite by cytochrome P450 2E1 in the C57B1 mouse, rats pretreated with a marginally toxic dose of DDTC prior to the administration of IDPN displayed olfactory mucosal damage, indicating that an alternative or additional pathway may be operative in the metabolism of IDPN and/or DDTC.
Deamer
N J
NJ
Department of Toxicology, North Carolina State University, Raleigh 27695-7633, USA.
Genter
M B
MB
D000704:Analysis of Variance; D000818:Animals; D001549:Benzamides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D019392:Cytochrome P-450 CYP2E1; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004221:Disulfiram / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D004050:Ditiocarb / Q000494:pharmacology* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D006540:Herbicides / Q000633:toxicity; D006900:Hydroxylation; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009498:Neurotoxins / Q000378:metabolism / Q000633:toxicity; D009570:Nitriles / Q000378:metabolism / Q000633:toxicity; D009596:Nitrophenols / Q000633:toxicity; D009831:Olfactory Mucosa / Q000187:drug effects* / Q000473:pathology; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D013045:Species Specificity
D001549:Benzamides; D065607:Cytochrome P-450 Enzyme Inhibitors; D006540:Herbicides; D009498:Neurotoxins; D009570:Nitriles; D009596:Nitrophenols; C008110:3,3'-iminodipropionitrile; D003577:Cytochrome P-450 Enzyme System; D004050:Ditiocarb; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; C055869:dichlobanil; D004221:Disulfiram; C024836:4-nitrophenol