ACEPHATE INSECTICIDE TOXICITY - SAFETY CONFERRED BY INHIBITION OF THEBIOACTIVATING CARBOXYAMIDASE BY THE METABOLITE METHAMIDOPHOS

Acephate is an important systemic organophosphorus insecticide with to xicity attributed to bioactivation on metabolic conversion to methamid ophos (or an oxidized metabolite thereof) which acts as an acetylcholi nesterase (AChE) inhibitor. The selective toxicity of acephate is cons idered to be due to facile conversion to methamidophos in insects but not mammals. We show in the present investigation that a carboxyamidas e activates acephate in mice and in turn undergoes inhibition by the h ydrolysis product, i.e., methamidophos; thus, the bioactivation is sta rted but immediately turned off. These relationships are established b y finding that 4 h pretreatment of mice with methamidophos ip at 5 mg/ kg has the following effects on acephate action: reduces methamidophos and acephate levels in liver by 30-60% in the first 2 h after ip acep hate dosage; inhibits the liver carboxyamidase cleaving [(CH3S)-C-14]a cephate to [ (CH3S)-C-14]methamidiphos with 50% block at similar to 1 mg/kg; strongly inhibits (CO2)-C-14 liberation from [(CH3C)-C-14(O)]ac ephate in. vivo; markedly alters the pattern of urinary metabolites of acephate by increasing O- and S-demethylation products retaining the carboxyamide moiety; greatly reduces the brain AChE inhibition followi ng acephate treatment; doubles the LD(50) Of ip-administered acephate from 540 to 1140 mg/kg. Methamidophos pretreatment in rats also marked ly alters the metabolism of dimethoate (another systemic insecticide) from principally carboxyamide hydrolysis to mainly other pathways. In contrast, methamidophos pretreatment of houseflies does not alter the acephate-induced toxicity and brain AChE inhibition. The safety of ace phate in mammals therefore appears to be due to conversion in small pa rt to methamidophos which, acting directly or as a metabolite, is a po tent carboxyamidase inhibitor, thereby blocking further activation.