The formamidine pesticides chlordimeform and amitraz decrease hepatic glutathione in mice through an interaction with alpha 2-adrenoceptors.
Recent studies have provided evidence that formamidine pesticides, such as chlordimeform (CDM; N'-4-chloro-o-tolyl-N,N-dimethylformamidine) or amitraz (AMZ; N'-2-4-(dimethylphenyl)-N-[((2,4-dimethylphenyl)imino)methyl]-N- methanimidamide) exert some of their toxic effects by an interaction with alpha 2-adrenoceptors. Since epinephrine and clonidine have been shown to decrease hepatic glutathione (GSH) by activating alpha 2-adrenoceptors, and alpha 2-antagonists partially antagonize GSH depletion and hepatotoxicity caused by bromobenzene and cocaine, we have investigated whether the formamidines would affect hepatic GSH levels in mice. Both CDM and AMZ decreased hepatic nonprotein sulfydryls (NPSH) to a maximum of about 40%, in a dose-dependent manner. The effect of AMZ was longer lasting than that of CDM. For both compounds, decrease of hepatic NPSH was antagonized by the alpha 2-antagonist yohimbine but not by the alpha 1-antagonist prazosin or the beta-antagonist propanolol. The alpha 2-agonist clonidine also caused a dose-dependent decrease of hepatic NPSH (to a maximum of 40%), which was prevented only by yohimbine. The effects of AMZ, CDM, and clonidine were not additive, suggesting that all compounds act on a common site and/or with a common mechanism. Adrenalectomy or destruction of peripheral sympathetic nerves with 6-hydroxydopamine did not alter the ability of CDM and AMZ to decrease hepatic NPSH. These results indicate that formamidine pesticides can affect the levels of hepatic GSH, possibly through a direct interaction with hepatic alpha 2-adrenoceptors.
Costa
L G
LG
Department of Environmental Health, University of Washington, Seattle 98195.
Gastel
J
J
Murphy
S D
SD
D000818:Animals; D002742:Chlorphenamidine / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D007306:Insecticides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects*; D014052:Toluidines / Q000633:toxicity*
D007306:Insecticides; D011942:Receptors, Adrenergic, alpha; D014052:Toluidines; C014983:amitraz; D005978:Glutathione; D002742:Chlorphenamidine