Mori T, Nakagawa A, Kobayashi N, Hashimoto M W, Wakabayashi K, Shimoi K, Kinae N
Radioisotope Center, Nara Medical University, Japan.
J Radiat Res. 1998 Mar;39(1):21-33. doi: 10.1269/jrr.39.21.
3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) is known to be a mutagen and carcinogen isolated from the charred parts of cooked foods. We found previously that Trp-P-1 enhanced UV-induced lethality and mutation frequency in Escherichia coli by inhibiting the repair of UV-induced DNA damage. In the present study, we investigated whether Trp-P-1 also potentiated UV-induced lethality by inhibiting the repair of UV-induced DNA damage in cultured mammalian cells. As a result, Trp-P-1 enhanced UV-induced lethality in a concentration-dependent manner in human and Chinese hamster cells. However, Trp-P-1 was unable to inhibit the repair of the two major photolesions (cyclobutane pyrimidine dimers and (6-4)photoproducts) from the genomic DNA, as determined using monoclonal antibodies specific for each type of lesion. On the other hand, Trp-P-1, with or without UV irradiation, efficiently suppressed DNA synthesis and arrested cells in S phase in concentration- and time-dependent manners, as measured by pulse-labelling with 3H-thymidine and flow cytometry. Thus, the present results suggest that Trp-P-1 potentiates UV-induced lethality in cultured mammalian cells by causing the S-phase arrest, not by inhibiting the repair of UV-induced DNA damage as observed in Escherichia coli.
3-氨基-1,4-二甲基-5H-吡啶并[4,3-b]吲哚（Trp-P-1）是一种从熟食烧焦部分分离出来的诱变剂和致癌物。我们之前发现，Trp-P-1通过抑制紫外线诱导的DNA损伤修复，增强了大肠杆菌中紫外线诱导的致死率和突变频率。在本研究中，我们调查了Trp-P-1是否也通过抑制培养的哺乳动物细胞中紫外线诱导的DNA损伤修复来增强紫外线诱导的致死率。结果，Trp-P-1在人和中国仓鼠细胞中以浓度依赖的方式增强了紫外线诱导的致死率。然而，使用针对每种损伤类型的单克隆抗体测定发现，Trp-P-1无法抑制基因组DNA中两种主要光损伤（环丁烷嘧啶二聚体和（6-4）光产物）的修复。另一方面，无论有无紫外线照射，Trp-P-1都能以浓度和时间依赖的方式有效抑制DNA合成，并使细胞停滞在S期，这通过用3H-胸腺嘧啶脉冲标记和流式细胞术来测量。因此，目前的结果表明，Trp-P-1通过导致S期停滞增强培养的哺乳动物细胞中紫外线诱导的致死率，而不是像在大肠杆菌中观察到的那样通过抑制紫外线诱导的DNA损伤修复。
