Inami Keiko, Miura Motofumi, Yoshida Masafumi, Mochizuki Masataka
Division of Pharmaceutical Organic Chemistry, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, 1-1-1 Daigakudori, Sanyo-Onoda-shi, Yamaguchi 756-0884, Japan.
Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba 278-8510, Japan.
Toxicol Res (Camb). 2023 May 23;12(3):503-506. doi: 10.1093/toxres/tfad036. eCollection 2023 Jun.
-Nitrosamines are well known as environmental carcinogens. We have reported that -nitroso--methylbutylamine was oxidized by Fe-Cu-HO to 5-methyl-5-nitro-1-pyrazoline, a direct-acting -oxide. 1-Pyrazolines have not been reported to exhibit genotoxicity. In this study, we investigated the effect of -oxidation on the mutagenicity of 1-pyrazolines using the Ames assay. The mutagenicity of 5-alkyl-5-nitro-1-pyrazoline 1-oxide (1a; methyl, 1b; ethyl), the -oxide isomer (3-alkyl-3-nitro-1-pyrazoline 1-oxide; 2a; methyl, 2b; ethyl), and the corresponding nonoxides (3-alkyl-3-nitro-1-pyrazoline; 3a; methyl, 3b; ethyl) was assayed in TA1535 and WP2. The ratios of mutagenic potency in TA1535 versus WP2 were compared with those of -alkylnitrosoureas. To predict the reaction site on the pyrazolines with nucleophiles, the electron density of the pyrazolines was obtained by theoretical calculations. The pyrazolines were mutagenic in TA1535 and WP2. The ratio of TA1535 to WP2 1a (87:13) or 1b (90:10) was similar to that of -ethyl--nitrosourea (70:30). In contrast, the mutagenic ratio of 2a (22:78) or 2b (52:48) was similar to that of -propyl--nitrosourea (48:52) or -butyl--nitrosourea (14:86). The ratio of 3a (53:47) or 3b (54:46) was similar to that of -propyl--nitrosourea or -butyl--nitrosourea. The pyrazolines exhibit genotoxicity, and the mutagenic potency of the 1-pyrazolines is influenced by -oxidation. We estimated that the mutagenicity of 1a or 1b was caused by DNA ethylation, and the isomers or the nonoxides were mutagenic via formation of alkylated DNA, which contains an alkyl chain longer than the propyl.
亚硝胺是众所周知的环境致癌物。我们曾报道过，亚硝基 - N - 甲基丁胺被铁 - 铜 - 水氧化为5 - 甲基 - 5 - 硝基 - 1 - 吡唑啉，一种直接作用的氧化物。尚未有报道称1 - 吡唑啉具有遗传毒性。在本研究中，我们使用艾姆斯试验研究了α - 氧化对1 - 吡唑啉致突变性的影响。在TA1535和WP2中测定了5 - 烷基 - 5 - 硝基 - 1 - 吡唑啉1 - 氧化物（1a；甲基，1b；乙基）、α - 氧化物异构体（3 - 烷基 - 3 -硝基 - 1 - 吡唑啉1 - 氧化物；2a；甲基，2b；乙基）以及相应的非氧化物（3 - 烷基 - 3 - 硝基 - 1 - 吡唑啉；3a；甲基，3b；乙基）的致突变性。将TA1535与WP2中的致突变效力比值与α - 烷基亚硝基脲的比值进行了比较。为了预测吡唑啉与亲核试剂的反应位点，通过理论计算获得了吡唑啉的电子密度。吡唑啉在TA1535和WP2中具有致突变性。TA1535与WP2中1a（87:13）或1b（90:10）的比值与N - 乙基 - N - 亚硝基脲（70:30）的比值相似。相比之下，2a（22:78）或2b（52:48）的致突变比值与N - 丙基 - N - 亚硝基脲（48:52）或N - 丁基 - N - 亚硝基脲（14:86）的比值相似。3a（53:47）或3b（54:46）的比值与N - 丙基 - N - 亚硝基脲或N - 丁基 - N - 亚硝基脲的比值相似。吡唑啉具有遗传毒性，并且1 - 吡唑啉的致突变效力受α - 氧化影响。我们估计1a或1b的致突变性是由DNA乙基化引起的，而异构体或非氧化物通过形成含有比丙基更长烷基链的烷基化DNA而具有致突变性。
