Okochi E, Namai E, Ito K, Mochizuki M
Kyoritsu College of Pharmacy, Tokyo, Japan.
Biol Pharm Bull. 1995 Jan;18(1):49-52. doi: 10.1248/bpb.18.49.
N-Nitrosodialkylamines are environmental alkylating carcinogens which are metabolically activated to alpha-hydroxy nitrosamines by cytochrome P450. The precise mechanism of their activation is not well understood, and a simplified chemical model for cytochrome P450 as a non-enzymatic system is useful for investigating the mechanism. In the present study, a chemical model was used in a bacterial mutation assay as a substitute of S9 mix, and its ability in the activation of N-nitrosodialkylamines was elucidated. In the presence of tetrakis(pentafluorophenyl)porphyrinatoiron(III) chloride and tert-butyl hydroperoxide, the mutagenicity of N-nitrosodialkylamines [alkyl = methyl (NDM), ethyl (NDE), propyl (NDP) and butyl (NDB)] in Salmonella typhimurium YG7108 was detected. The mutagenicity increased by the pre-incubation and was dependent on the concentration of mutagens. The mutagenic activity of N-nitrosodialkylamines in Salmonella typhimurium YG7108 was in the following order: NDB > NDM > NDE approximately NDP. The formation of aldehydes derived from dealkylation in the present model was exemplified by the formation of acetaldehyde from NDE. These results showed that N-nitrosodialkylamines were activated by the model system, and consequent mutagenicity was observed. The oxidation by the model can mimic the metabolic activation of chemical carcinogens by cytochrome P450, and the biomimetic catalyst is useful in investigating the mechanisms of the metabolic pathway of N-nitrosodialkylamines.
N-亚硝基二烷基胺是环境烷基化致癌物，可通过细胞色素P450代谢活化为α-羟基亚硝胺。其活化的确切机制尚不清楚，将细胞色素P450作为非酶系统的简化化学模型有助于研究该机制。在本研究中，一种化学模型被用于细菌突变试验以替代S9混合物，并阐明了其活化N-亚硝基二烷基胺的能力。在四（五氟苯基）卟啉铁（III）氯化物和叔丁基过氧化氢存在下，检测了N-亚硝基二烷基胺[烷基 = 甲基（NDM）、乙基（NDE）、丙基（NDP）和丁基（NDB）]在鼠伤寒沙门氏菌YG7108中的致突变性。预孵育后致突变性增加，且依赖于诱变剂的浓度。N-亚硝基二烷基胺在鼠伤寒沙门氏菌YG7108中的诱变活性顺序如下：NDB > NDM > NDE ≈ NDP。本模型中脱烷基产生的醛的形成以NDE形成乙醛为例。这些结果表明，N-亚硝基二烷基胺被该模型系统活化，并观察到了相应的致突变性。该模型的氧化作用可模拟细胞色素P450对化学致癌物的代谢活化，这种仿生催化剂有助于研究N-亚硝基二烷基胺代谢途径的机制。
