Abstract:
Isoprocarb (IPC), one of the most important carbamate pesticides, is used to control pests, such as rice planthoppers in crops. Studies have found that IPC induced hepatotoxicity in poultry chicken. However, the mechanisms of IPC-induced hepatotoxicity are unclear. The objectives of this study were to characterize reactive metabolites of IPC in vitro and in vivo, to identify cytochrome P450 enzymes for metabolic activation, and to define a possible correlation between the metabolic activation and cytotoxicity of IPC. In GSH- or NAC-supplemented microsomal incubations, one GSH conjugate (M6) and two NAC conjugates (M7 and M8) were detected after exposure to IPC. The corresponding GSH conjugate and NAC conjugates were found in the liver homogenates and urine of mice after IPC administration. IPC was found to be metabolized to a quinone intermediate reactive to GSH in vitro and in vivo. IPC was found to induce marked cytotoxicity in cultured mouse primary hepatocytes. Ketoconazole, a selective CYP3A4/5 enzyme inhibitor, attenuated the susceptibility of hepatocytes to IPC cytotoxicity.
摘要:
异丙威(IPC),最重要的氨基甲酸酯农药之一,是用来控制害虫的,如作物中的稻飞虱。研究发现IPC可引起禽鸡的肝毒性。然而,IPC诱导的肝毒性的机制尚不清楚。本研究的目的是在体外和体内表征IPC的反应性代谢物,鉴定细胞色素P450酶的代谢激活,并定义IPC的代谢激活与细胞毒性之间可能的相关性。在GSH或NAC补充的微粒体孵育中,在暴露于IPC后检测到一个GSH缀合物(M6)和两个NAC缀合物(M7和M8)。在IPC给药后,在小鼠的肝匀浆和尿中发现了相应的GSH缀合物和NAC缀合物。发现IPC在体外和体内代谢为与GSH反应的醌中间体。发现IPC在培养的小鼠原代肝细胞中诱导显著的细胞毒性。酮康唑,一种选择性CYP3A4/5酶抑制剂,减弱肝细胞对IPC细胞毒性的敏感性。