Abstract：
N-Nitrosamines, known as drug impurities and suspected carcinogens, have drawn significant public concern. In response to drug regulatory needs, the European Medicines Agency (EMA) has previously proposed a carcinogenic potency categorization approach based on the N-nitrosamine α-hydroxylation hypothesis, i.e., that N-nitrosamine mutagenicity increases with the number of α-hydrogen atoms. However, this structure-activity relationship has not been fully tested in vivo. NEIPA (N-nitrosoethylisopropylamine) and NDIPA (N-nitrosodiisopropylamine) are small N-Nitrosamines with similar structures, differing in that the former compound has an additional α-hydrogen atom. In this study, NEIPA and NEIPA doses, 25-100 mg/kg, were administered orally to C57BL/6 J mice for seven consecutive days, and their mutation and DNA damage effects were compared. Compared with NDIPA, the mutagenicity and DNA damage potencies of NEIPA (which contains one more α-hydrogen) were much greater. These differences may be related to their distinct metabolic pathways and target organs. This case study confirms the role of α-hydroxyl modification in the mutagenicity of nitrosamines, with oxidation at the α-hydrogen being a crucial step in the formation of mutagens from N-Nitrosamines, and can inform mutagenicity risk assessment and the formulation of regulatory standards for N-nitrosamine impurities.
摘要：
N-亚硝胺,被称为药物杂质和可疑致癌物，引起了公众的极大关注。为了满足药品监管的需要，欧洲药品管理局（EMA）先前提出了一种基于N-亚硝胺α-羟基化假说的致癌效力分类方法，即，N-亚硝胺的诱变性随着α-氢原子的数量而增加。然而,这种结构-活性关系尚未在体内得到充分测试。NEIPA（N-亚硝基乙基异丙胺）和NDIPA（N-亚硝基二异丙胺）是具有相似结构的小N-亚硝胺，不同之处在于前者化合物具有额外的α-氢原子。在这项研究中,NEIPA和NEIPA剂量，25-100mg/kg,连续7天口服给C57BL/6J小鼠，并比较了它们的突变和DNA损伤效应。与NDIPA相比,NEIPA（含有一个额外的α-氢）的诱变性和DNA损伤效力更大。这些差异可能与其不同的代谢途径和靶器官有关。本案例研究证实了α-羟基修饰在亚硝胺致突变性中的作用，α-氢的氧化是N-亚硝胺形成诱变剂的关键步骤，并可以为诱变风险评估和N-亚硝胺杂质监管标准的制定提供信息。
