The formamidine pesticides chlordimeform and amitraz decrease hepatic glutathione in mice through an interaction with alpha2‐adrenoceptors

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Abstract
Recent studies have provided evidence that formamidine pesticides, such as chlordi‐meform (CDM; N‘‐chloro‐o‐tolyl‐N,N‐dimethylformamidine) oramitraz (AMZ; N‘‐2–4‐(dimethylphenyl)‐N[((2,4‐dimethylphenyl)imino)methyl]‐N‐methanimidamide) exert some of their toxic effects by an interaction with alpha2‐adrenoceptors. Since epinephrine and clonidine have been shown to decrease hepatic glutathione (CSH) by activating alpha2‐adrenoceptors, and alpha2‐antagonists partially antagonize GSH depletion and hepatotoxicity caused by bromobenzene and cocaine, we have investigated whether the formamidines would affect hepatic CSH 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 alpha2‐antagonist prazosin or the beta‐antagonist propanolol. The alpha2‐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 CSH, possibly through a direct interaction with hepatic alpha2‐adrenoceptors.