Mahajna M, Quistad G B, Casida J E
Department of Environmental Science, Policy, and Management, University of California, Berkeley 94720-3112, USA.
Chem Res Toxicol. 1997 Jan;10(1):64-9. doi: 10.1021/tx9601420.
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.
乙酰甲胺磷是一种重要的内吸性有机磷杀虫剂，其毒性归因于代谢转化为甲胺磷（或其氧化代谢物）时的生物活化作用，甲胺磷可作为乙酰胆碱酯酶（AChE）抑制剂。乙酰甲胺磷的选择性毒性被认为是由于其在昆虫体内易于转化为甲胺磷，而在哺乳动物体内则不然。我们在本研究中表明，一种羧酰胺酶可在小鼠体内激活乙酰甲胺磷，进而被水解产物即甲胺磷抑制；因此，生物活化作用开始后立即停止。这些关系是通过以下发现确立的：以5mg/kg的剂量腹腔注射甲胺磷对小鼠进行4小时预处理，对乙酰甲胺磷的作用有以下影响：在腹腔注射乙酰甲胺磷后的头2小时内，肝脏中甲胺磷和乙酰甲胺磷水平降低30 - 60%；抑制肝脏羧酰胺酶将[14CH3S]乙酰甲胺磷裂解为[14CH3S]甲胺磷，在约1mg/kg时出现50%的阻断；在体内强烈抑制[CH3(14)C(O)]乙酰甲胺磷释放14CO2；通过增加保留羧酰胺部分的O - 和S - 去甲基化产物，显著改变乙酰甲胺磷的尿代谢物模式；大大降低乙酰甲胺磷处理后对脑AChE的抑制作用；使腹腔注射乙酰甲胺磷的LD50从540mg/kg增加到1140mg/kg。大鼠经甲胺磷预处理后，也显著改变了乐果（另一种内吸性杀虫剂）的代谢，从主要的羧酰胺水解转变为主要的其他途径。相比之下，家蝇经甲胺磷预处理后，乙酰甲胺磷诱导的毒性和对脑AChE的抑制作用并未改变。因此，乙酰甲胺磷在哺乳动物体内的安全性似乎部分归因于其少量转化为甲胺磷，甲胺磷直接或作为代谢物是一种有效的羧酰胺酶抑制剂，从而阻断了进一步的活化。
