Wei Y D, Helleberg H, Rannug U, Rannug A
Department of Genetic and Cellular Toxicology, Stockholm University, Sweden.
Chem Biol Interact. 1998 Mar 12;110(1-2):39-55. doi: 10.1016/s0009-2797(97)00111-7.
Studies to assess the induction of CYP1A1 gene expression by tryptophan derived oxidation products which are suggested as endogenous ligands for the Ah receptor are described. For the two high affinity Ah receptor ligands produced from tryptophan, the chemical structure was recently identified as 6-formylindolo[3,2-b]carbazole (FICZ) and 6,12-diformylindolo[3,2-b]carbazole (dFICZ), respectively. Therefore these two compounds show a close similarity to the indolecarbinol-derived condensation product indolo[3,2-b]carbazole (ICZ). Incubation of cells from a human keratinocyte (HaCaT) cell line together with ICZ, FICZ, dFICZ and some structurally related indole compounds was performed. The compound with the highest affinity to the Ah receptor, FICZ, was found to be the most efficient inducer of CYP1A1 gene expression in short time incubation (0.5 h) experiments. With longer incubation times (24 h) ICZ was the most efficient inducer. The two most active compounds, FICZ and ICZ, caused increased mRNA levels already at a concentration of 100 pM. FICZ was also shown to increase CYP1A1 mRNA levels in fresh human peripheral blood cells at the same low concentration. FICZ and ICZ were furthermore compared with regard to their capacity to inhibit cDNA-expressed human CYP1A1 enzyme and FICZ was found to be the most potent inhibitor. The inhibition was, however, transient in character indicating that FICZ is also an exceptionally good substrate for the CYP1A1 enzyme. The results showing the potent and transient effect of these formylindolocarbazoles, thus emphasize their important properties as signal substances in the Ah receptor pathway. This makes the most potent compound, FICZ, a good candidate for the endogenous ligand of the Ah receptor necessary for normal development and for the basal expression of Ah receptor-dependent genes.
本文描述了一些研究，旨在评估色氨酸衍生的氧化产物对CYP1A1基因表达的诱导作用，这些氧化产物被认为是芳烃受体（Ah受体）的内源性配体。对于由色氨酸产生的两种高亲和力Ah受体配体，其化学结构最近分别被鉴定为6-甲酰基吲哚并[3,2-b]咔唑（FICZ）和6,12-二甲酰基吲哚并[3,2-b]咔唑（dFICZ）。因此，这两种化合物与吲哚甲醇衍生的缩合产物吲哚并[3,2-b]咔唑（ICZ）具有密切的相似性。将人角质形成细胞（HaCaT）细胞系的细胞与ICZ、FICZ、dFICZ以及一些结构相关的吲哚化合物一起孵育。在短时间孵育（0.5小时）实验中，发现对Ah受体亲和力最高的化合物FICZ是CYP1A1基因表达的最有效诱导剂。在较长孵育时间（24小时）时，ICZ是最有效的诱导剂。两种最具活性的化合物FICZ和ICZ，在浓度为100 pM时就已导致mRNA水平升高。FICZ还显示在相同低浓度下可增加新鲜人外周血细胞中CYP1A1 mRNA水平。此外，还比较了FICZ和ICZ抑制cDNA表达的人CYP1A1酶的能力，发现FICZ是最有效的抑制剂。然而，这种抑制具有短暂性，表明FICZ也是CYP1A1酶的一种异常良好的底物。这些结果表明这些甲酰基吲哚咔唑具有强大而短暂的作用效果，从而强调了它们作为Ah受体途径中信号物质的重要特性。这使得最有效的化合物FICZ成为正常发育以及Ah受体依赖性基因基础表达所必需的Ah受体内源性配体的良好候选者。
