Funayama Y, Nishio K, Wakabayashi K, Nagao M, Shimoi K, Ohira T, Hasegawa S, Saijo N
Pharmacology Division, National Cancer Center Research Institute, Tokyo 104, Japan.
Mutat Res. 1996 Feb 1;349(2):183-91. doi: 10.1016/0027-5107(95)00176-x.
beta-Carbolines, harman (1-methyl-9H-pyrido[3,4-b]indole) and norharman (9H-pyrido[3,4-b]indole) and gamma-carbolines, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 3-amino-4-methyl-5H-pyrido[4,3-b]indole (Trp-P-2), are present in cooked foods and cigarette smoke. We studied the effects of these heterocyclic amines on the activity of DNA topoisomerases. Trp-P-1 and Trp-P-2 inhibited topoisomerase I (topo I) activity with ED50 values of 1.48 and 1.55 micrograms/ml, respectively, in a relaxation assay. Harman and norharman inhibited topo I activity but with much higher ED50 values, 23.8 and 34.4 micrograms/ml, respectively. Trp-P-1 and Trp-P-2 also inhibited topoisomerase II (topo II) activity at about 50 micrograms/ml, in a decatenation assay. Harman and norharman showed a much lower inhibitory effect on topo II activity. None of these compounds stabilized the cleavable complex mediated by topo II. Trp-P-1 and Trp-P-2 intercalated into DNA at concentrations inhibitory to topoisomerases. We considered that the intercalation with DNA and the inhibition of DNA topoisomerases by heterocyclic amines might be partly related to their inhibition of DNA excision repair and their enhancing effect on UV- or chemically induced mutagenic activity.
β-咔啉、哈尔满（1-甲基-9H-吡啶并[3,4-b]吲哚）和去甲哈尔满（9H-吡啶并[3,4-b]吲哚）以及γ-咔啉、3-氨基-1,4-二甲基-5H-吡啶并[4,3-b]吲哚（Trp-P-1）和3-氨基-4-甲基-5H-吡啶并[4,3-b]吲哚（Trp-P-2）存在于熟食和香烟烟雾中。我们研究了这些杂环胺对DNA拓扑异构酶活性的影响。在松弛试验中，Trp-P-1和Trp-P-2抑制拓扑异构酶I（拓扑I）活性，其半数有效剂量（ED50）值分别为1.48和1.55微克/毫升。哈尔满和去甲哈尔满也抑制拓扑I活性，但ED50值高得多，分别为23.8和34.4微克/毫升。在解连环试验中，Trp-P-1和Trp-P-2在约50微克/毫升时也抑制拓扑异构酶II（拓扑II）活性。哈尔满和去甲哈尔满对拓扑II活性的抑制作用要低得多。这些化合物均未稳定由拓扑II介导的可切割复合物。Trp-P-1和Trp-P-2在抑制拓扑异构酶的浓度下插入DNA。我们认为，杂环胺与DNA的插入以及对DNA拓扑异构酶的抑制可能与其对DNA切除修复的抑制作用及其对紫外线或化学诱导的诱变活性的增强作用部分相关。
