Acephate insecticide toxicity: safety conferred by inhibition of the bioactivating carboxyamidase by the metabolite methamidophos.

Acephate is an important systemic organophosphorus insecticide with toxicity attributed to bioactivation on metabolic conversion to methamidophos (or an oxidized metabolite thereof) which acts as an acetylcholinesterase (AChE) inhibitor. The selective toxicity of acephate is considered to be due to facile conversion to methamidophos in insects but not mammals. We show in the present investigation that a carboxyamidase activates acephate in mice and in turn undergoes inhibition by the hydrolysis product, i.e., methamidophos; thus, the bioactivation is started but immediately turned off. These relationships are established by finding that 4 h pretreatment of mice with methamidophos i.p. 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 i.p. acephate dosage; inhibits the liver carboxyamidase cleaving [14CH3S]acephate to [14CH3S]methamidiphos with 50% block at approximately 1 mg/kg; strongly inhibits 14CO2 liberation from [CH3(14)C(O)]acephate 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 following acephate treatment; doubles the LD50 of i.p.-administered acephate from 540 to 1140 mg/kg. Methamidophos pretreatment in rats also markedly 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 acephate in mammals therefore appears to be due to conversion in small part to methamidophos which, acting directly or as a metabolite, is a potent carboxyamidase inhibitor, thereby blocking further activation.