Data on the bioactivation of Phosmet (Pho), a phthalimide-derived organophosphate pesticide (OPT), to the neurotoxic metabolite Phosmet-oxon (PhOx) in human are not available. The characterization of the reaction in single human recombinant CYPs evidenced that the ranking of the intrinsic clearances was: 2C18>2C19>2B6>2C9>1A1>1A2>2D6>3A4>2A6. Considering the average human hepatic content, CYP2C19 contributed for the great majority (60%) at relevant exposure concentrations, while CYP2C9 (33%) and CYP3A4 (31%) were relevant at high substrate concentration. The dose-dependent role of the active isoforms was confirmed in human liver microsomes by using selective CYP inhibitors. This prominent role of CYP2C in oxon formation was not shared by other OPTs. The pre-systemic Pho bioactivation measured in human intestinal microsomes was relevant accounting for ¼ of that measured in the liver showing two reaction phases catalysed by CYP2C and CYP3A4. Phosmet efficiently inhibited CPF bioactivation and detoxication, with Ki values (≈30 μM) relevant to pesticide concentrations achievable in the human liver, while the opposite is unlikely (Ki ≈ 160 μM) at the actual exposure levels, depending on the peculiar isoform-specific Pho bioactivation. Kinetic information in humans can support the development of quantitative in vitro/in vivo extrapolation and in silico models for risk assessment refinement for single and multiple pesticides.

目前尚无关于邻苯二甲酰亚胺衍生的有机磷酸酯农药（OPT）Phosmet（Pho）对人的神经毒性代谢产物Phosmet-oxon（PhOx）的生物激活数据。在单个人重组CYP中反应的特征表明，固有清除率的等级为：2C18> 2C19> 2B6> 2C9> 1A1> 1A2> 2D6> 3A4> 2A6。考虑到人类平均肝脏含量，CYP2C19在相关暴露浓度下占绝大多数（60％），而CYP2C9（33％）和CYP3A4（31％）在高底物浓度下具有相关性。通过使用选择性CYP抑制剂在人肝微粒体中证实了活性同工型的剂量依赖性作用。CYP2C在牛氧体形成中的这种突出作用未被其他OPT共有。在人肠道微粒体中测得的系统前Pho生物活化是相关的，占在肝脏中测得的1/4，显示出CYP2C和CYP3A4催化的两个反应阶段。Phosmet有效抑制了CPF的生物活化和解毒作用，Ki值（约30μM）与人体肝脏中的农药浓度有关，而在实际暴露水平下，相反的可能性（Ki≈160μM）则不太可能，这取决于特定的同工型Pho生物激活。人类的动力学信息可以支持定量研究的发展 而根据实际的异构体特异性Pho生物激活，在实际暴露水平下相反的情况（Ki≈160μM）不太可能。人类的动力学信息可以支持定量研究的发展 而根据实际的异构体特异性Pho生物激活，在实际暴露水平下相反的情况（Ki≈160μM）不太可能。人类的动力学信息可以支持定量研究的发展体外/体内外推法和计算机模拟模型，用于完善单一和多种农药的风险评估。