The chemistry and biology of 7H-dibenzo[c,g]carbazole: synthesis and characterization of selected derivatives, metabolism in rat liver preparations and mutagenesis mediated by cultured rat hepatocytes.
The chemistry and biology of 7H-dibenzo[c,g]carbazole: synthesis and characterization of selected derivatives, metabolism in rat liver preparations and mutagenesis mediated by cultured rat hepatocytes.
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7H-二苯并[c,g]咔唑的化学和生物学：所选衍生物的合成和表征、大鼠肝脏制剂中的代谢以及培养的大鼠肝细胞介导的诱变。
DOI：
10.1093/carcin/10.3.419
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发表时间：
1989
期刊：
影响因子：
4.7
通讯作者：
Warshawsky,D
中科院分区：
文献类型：
--
作者：
Stong,DB;Christian,RT;Jayasimhulu,K;Wilson,RM;Warshawsky,D
合成了 7H-二苯并[c, g]咔唑 (DBC)（一种强效环境致癌物）的真实稳定标准品，以研究该化合物在整个细胞系统中的代谢和诱变。通过 UV、IR、荧光和高分辨率 NMR 光谱以及高分辨率质谱程序完成了 2-OH-DBC、3-OH-DBC、4-OH-DBC、13c-OH-DBC 和 N-甲基-DBC 的完整表征。通过 HPLC 从大鼠肝微粒体培养物提取物和大鼠肝细胞原代培养物的培养基中分离和分离 DBC 代谢物。通过紫外和荧光光谱、质谱分析以及共色谱技术比较真实标准品和分离的代谢物来完成代谢物的鉴定。在所有大鼠肝脏制剂中都发现了 2-OH-DBC 和 3-OH-DBC 以及其他三种未鉴定的酚类。在任何条件下均未分离出4-OH-DBC、13c-OH-DBC或N-甲基-DBC。将大鼠肝细胞培养物中 DBC 代谢物的出现率与 10、25、50 和 100 μM 底物的苯并[a]芘 (BaP) 的出现率进行比较。当底物浓度为 25 μM 或更高时，DBC 代谢物在培养基中的出现速度明显快于 BaP。在 100 μM 底物下，DBC 代谢物的出现速度是 BaP 观察到的速度的 4 倍。在大鼠肝细胞和上皮细胞系共培养系统中，在相同条件下将 DBC 与 BaP 的诱变潜力进行比较时，发现在培养基中浓度为 0.4、4.0 和 40.0 μM 时，DBC 产生的诱变率明显高于 BaP。将 DBC 的诱变潜力与母体化合物的几种衍生物进行了比较。 3-OH-DBC、13c-OH-DBC 和 N-methyl-DBC 在 40 μM 浓度的共培养系统中被发现具有诱变性，突变频率分别为每 105 个幸存者中 4.4 ± 0.8、8.0 ±3.1 和 12.9 ± 5.4 个突变体。在相同浓度下，母体化合物每 105 个幸存者诱导 8.0 ± 2.8 个突变体。 2-OH-DBC和4-OH-DBC在相同条件下不致突变。研究表明，7H-DBC 的代谢主要导致大鼠肝细胞中的酚类物质产生。诱变实验的结果表明，在所研究的衍生物中，那些与氮诱导相关的衍生物具有诱变性。后面的研究表明氮通过诱导机制参与母体化合物的活化。
Authentic stable standards of 7H-dibenzo[c, g]carbazole (DBC), a potent environmental carcinogen, were synthesized in order to study the compound's metabolism and mutagenesis in whole cell systems. Complete characterization of 2-OH-DBC, 3-OH-DBC, 4-OH-DBC, 13c-OH-DBC and N-methyl-DBC was accomplished by UV, IR, fluorescence and high resolution NMR spectra, and by high resolution mass spectrometric procedures. Metabolites of DBC were isolated and separated by HPLC from extracts of rat liver microsomal incubations and the medium of primary cultures of rat liver cells. Identification of metabolites was accomplished by comparisons between the authentic standards and isolated metabolites by UV and fluorescence spectroscopy, mass spectral analyses, and by co-chromatographic techniques. 2-OH-DBC and 3-OH-DBC were found in all rat liver preparations as well as three other unidentified phenols. 4-OH-DBC, 13c-OH-DBC orN-methyl-DBC were not isolated under any conditions. The rates of appearance of DBC metabolites in cultures of rat liver cells were compared to those for benzo[a]pyrene (BaP) at 10, 25, 50 and 100 μM substrate. At 25 μM substrate or greater, DBC metabolites appeared in the culture medium at significantly faster rates than those of BaP. At 100 μM substrate, DBC metabolites appeared at a rate ∼4-times the rate observed for BaP. When the mutagenk potential of DBC was compared to that of BaP under identical conditions in a co-cultivation system of rat liver cells and an epithelial cell line, DBC was found to produce significantly higher rates of mutagenesis than BaP at concentrations of 0.4, 4.0 and 40.0 μM in the culture medium. The mutagenic potential of DBC was compared to that of several derivatives of the parent compound. 3-OH-DBC, 13c-OH-DBC and N-methyl-DBC were found to be mutagenic in the co-cultivation system at 40 μM, with mutation frequencies of 4.4 ± 0.8, 8.0 ±3.1 and 12.9 ± 5.4 mutants per 105 survivors, respectively. The parent compound induced 8.0 ± 2.8 mutants per 105survivors at the same concentration. 2-OH-DBC and 4-OH-DBC were not mutagenic under the same conditions. The studies have shown that metabolism of 7H-DBC leads predominantly to phenols in rat liver cells. The results of the mutagenesis experiments indicate that, of the derivatives studied, those associated by induction to the nitrogen are mutagenic. The latter studies suggest that the nitrogen is involved in the activation of the parent compound through inductive mechanisms.