Emerit I, Levy A, Cerutti P
Mutat Res. 1983 Aug;110(2):327-35. doi: 10.1016/0027-5107(83)90149-5.
To gain insight into the mechanism of formation of chromosomal aberrations by the tumor promoter phorbolmyristate acetate (PMA) in human lymphocytes, we investigated the effect of antioxidants and inhibitors of arachidonic acid metabolism. Among the antioxidants bovine erythrocyte CuZn superoxide dismutase, glutathione peroxidase, mannitol (a scavenger of hydroxyl radicals), butylated hydroxytoluene and butylated hydroxyanisole were anticlastogenic while catalase and dimethylfuran (a scavenger of singlet oxygen) were inactive. These results show that the induction of aberrations by PMA occurs via indirect action, i.e. the intermediacy of superoxide and hydroxyl radicals. The following inhibitors of arachidonic acid metabolism were strongly anticlastogenic: the cyclo-oxygenase inhibitors indomethacin and flufenamic acid and the lipoxygenase inhibitor BN1015. Imidazole, nordihydroguaiaretic acid BN1048 and 5,8,11,14-eicosatetraynoic acid were moderately active. The inhibitor of phospholipase A2, fluocinolone acetonide, was also anticlastogenic. We conclude that the oxidative metabolism of arachidonic acid is involved in the induction of chromosomal aberrations by PMA in human lymphocytes. However, because of the limited selectivity of these drugs, it is not yet possible to identify unambiguously the step(s) in the arachidonic acid cascade responsible for PMA clastogenicity.
为深入了解肿瘤启动子佛波酯肉豆蔻酸乙酸酯（PMA）在人淋巴细胞中诱导染色体畸变的机制，我们研究了抗氧化剂和花生四烯酸代谢抑制剂的作用。在抗氧化剂中，牛红细胞铜锌超氧化物歧化酶、谷胱甘肽过氧化物酶、甘露醇（一种羟基自由基清除剂）、丁基羟基甲苯和丁基羟基茴香醚具有抗断裂作用，而过氧化氢酶和二甲基呋喃（一种单线态氧清除剂）则无活性。这些结果表明，PMA诱导的畸变是通过间接作用发生的，即超氧化物和羟基自由基的介导作用。以下花生四烯酸代谢抑制剂具有很强的抗断裂作用：环氧化酶抑制剂吲哚美辛和氟芬那酸以及脂氧合酶抑制剂BN1015。咪唑、去甲二氢愈创木酸BN1048和5,8,11,14-二十碳四炔酸活性中等。磷脂酶A2抑制剂氟轻松丙酮也具有抗断裂作用。我们得出结论，花生四烯酸的氧化代谢参与了PMA在人淋巴细胞中诱导染色体畸变的过程。然而，由于这些药物的选择性有限，目前还无法明确确定花生四烯酸级联反应中导致PMA致断裂性的具体步骤。
