The formamidine pesticides chlordimeform and amitraz decrease hepatic glutathione in micethrough an interaction with alpha2-adrenoceptors

Recent studies have provided evidence that formamidine pesticides, such as chlordi meform (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 ¡-adrenoceptors. Since epi nephrine and clonidine have been shown to decrease hepatic glutathione (GSH) by activating alpha2-adrenoceptors, and alpha2-antagonists partially antagonize GSH de pletion and hepatotoxicity caused bybromobenzene and cocaine, we have investi gated 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 alpha2-antagonist yohimbine but not by the alph1-arantagonist prazosin or the beta antagonist propanolol. The alpharagonist 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. Adre nalectomy or destruction of peripheral sympathetic nerves with 6-hydroxydopamine did not alter the ability of CDM and AMZ to decrease hepaticNPSH. These results indicate that formamidine pesticides can affect the levels of hepatic GSH, possibly through a direct interaction with hepatic alpha2-adrenoceptors. © 1988 by Hemisphere Publishing Corporation.