Giri A K, Messerly E A, Chakraborty P K, Hooberman B H, Sinsheimer J E
College of Pharmacy, University of Michigan, Ann Arbor 48109-1065.
Mutat Res. 1990 Nov;242(3):187-94. doi: 10.1016/0165-1218(90)90084-f.
Four aliphatic epoxides, 1-naphthyl glycidyl ether (NGE), 1-naphthylpropylene oxide (NPO), 4-nitrophenyl glycidyl ether (NPGE), 3,3,3-trichloropropylene oxide (TCPO) and two of their precursors, 1-allylnaphthalene (AN) and 3,3,3-trichloropropylene (TCP), were selected for DNA strand-break analysis in liver in vivo with mice. The four epoxides selected were among the most mutagenic aliphatic epoxides in our previous structure-mutagenicity studies with the Ames test and had been evaluated for their in vivo genotoxicity as measured by sister-chromatid exchange (SCE) and chromosome aberrations (CA). A significant increase in the percentage of unwound DNA was observed at a 4-h exposure time for all the compounds at high doses except for AN. TCPO, the least genotoxic compound in bone marrow, had the greatest liver toxicity after 1-h exposure while NGE showed the most toxicity after 6 h. As might be expected from their corresponding epoxides, AN but not TCP exhibited significant SCE activity in the bone marrow of mice. This study reemphasizes the importance of evaluating the stability of direct-acting alkylating agents in comparing test results and in establishing the relative order of genotoxicity for such compounds.
选取了四种脂肪族环氧化物，即1-萘基缩水甘油醚（NGE）、1-萘基环氧丙烷（NPO）、4-硝基苯基缩水甘油醚（NPGE）、3,3,3-三氯环氧丙烷（TCPO）以及它们的两种前体，1-烯丙基萘（AN）和3,3,3-三氯丙烯（TCP），用于在小鼠体内肝脏中进行DNA链断裂分析。所选取的这四种环氧化物是我们先前用艾姆斯试验进行结构-致突变性研究中最具致突变性的脂肪族环氧化物，并且已通过姐妹染色单体交换（SCE）和染色体畸变（CA）对它们的体内遗传毒性进行了评估。除AN外，所有化合物在高剂量下暴露4小时后，观察到解旋DNA百分比显著增加。TCPO是骨髓中遗传毒性最小的化合物，暴露1小时后肝脏毒性最大，而NGE在6小时后毒性最大。正如从它们相应的环氧化物中可能预期的那样，AN而非TCP在小鼠骨髓中表现出显著的SCE活性。这项研究再次强调了在比较试验结果以及确定此类化合物遗传毒性的相对顺序时，评估直接作用烷基化剂稳定性的重要性。
