Okazaki O, Persmark M, Guengerich F P
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146.
Chem Res Toxicol. 1993 Mar-Apr;6(2):168-73. doi: 10.1021/tx00032a005.
N-Nitroso-N-methylvinylamine was synthesized and treated with dimethyldioxirane to produce 1-(N-nitrosomethylamino)oxirane. 1-(N-Nitrosomethylamino)oxirane had a t1/2 of < 5 s in buffer at neutral pH and 23 degrees C. This epoxide reacted with Ado to form 1,N6-etheno(epsilon-)Ado. It also reacted with DNA to form products arising from the oxirane portion of the molecule [N7-(2-oxoethyl)Gua,N2,3-epsilon-Gua, and 1,N6-epsilon-dAdo] and the methyl group (N7-methylGua). NADPH-fortified rat liver microsomes oxidized N-nitroso-N-methylvinylamine to form 1,N6-epsilon-Ado in the presence of Ado. Further, 1,N6-epsilon-Ado was also formed in microsomal incubations containing N-nitroso-N-methylethylamine, indicating that desaturation of the ethyl moiety occurs to form a vinyl group and then an epoxide. When NADPH-fortified microsomes were incubated with N-nitroso-N-methylvinylamine, HCHO was formed, and when DNA was included in incubations, 1,N6-epsilon-dAdo and N7-methylGua were isolated from DNA. In the cases of both HCHO and N7-methylGua, product formation was similar to the levels seen with N-nitroso-N,N-dimethylamine and N-nitroso-N-methylethylamine.
合成了N-亚硝基-N-甲基乙烯胺,并用二甲基二氧杂环丙烷处理以生成1-(N-亚硝基甲基氨基)环氧乙烷。1-(N-亚硝基甲基氨基)环氧乙烷在中性pH值和23摄氏度的缓冲液中的半衰期小于5秒。该环氧化物与腺苷反应形成1,N6-乙烯基(ε)-腺苷。它还与DNA反应形成由分子的环氧乙烷部分产生的产物[N7-(2-氧代乙基)鸟嘌呤、N2,3-ε-鸟嘌呤和1,N6-ε-脱氧腺苷]以及甲基(N7-甲基鸟嘌呤)。用NADPH强化的大鼠肝微粒体在腺苷存在下将N-亚硝基-N-甲基乙烯胺氧化形成1,N6-ε-腺苷。此外,在含有N-亚硝基-N-甲基乙胺的微粒体孵育中也形成了1,N6-ε-腺苷,这表明乙基部分发生去饱和形成乙烯基,然后形成环氧化物。当用NADPH强化的微粒体与N-亚硝基-N-甲基乙烯胺一起孵育时,会形成甲醛,当孵育中加入DNA时,从DNA中分离出1,N6-ε-脱氧腺苷和N7-甲基鸟嘌呤。在甲醛和N7-甲基鸟嘌呤的情况下,产物形成水平与用N-亚硝基-N,N-二甲基胺和N-亚硝基-N-甲基乙胺时观察到的水平相似。