Abstract The objective of the study was to investigate the (anti)estrogenic, (anti)androgenic and aryl hydrocarbon receptor (AhR) agonistic activities of a mixture of acid condensation products of indole-3-carbinol, termed RXM, and to identify the compounds most responsible for the observed effects, using in vitro receptor-reporter gene transcriptional activation bioassays. For this, HPLC-fractions of RXM were prepared and tested. LC-MS/MS analysis was carried out for the identification of some of the acid condensation products. The RXM displayed weak estrogenic and anti-androgenic, and strong AhR agonistic properties. The fraction containing 3,3-diindolylmethane (DIM) displayed a weak estrogenic and relatively strong anti-androgenic activity. DIM was confirmed to be an androgen receptor (hAR) antagonist and a partial estrogen receptor (hERα) agonist. Also the fraction containing the trimer [2-(indol-3-ylmethyl)indol-3-yl]indol-3-ylmethane (LTr1) showed anti-androgenic activities. It was shown for the first time that DIM is not only estrogenic and anti-androgenic, but also possesses anti-estrogenic properties. Though indolo[3,2-b]carbazole (ICZ) is a potent AhR activator and was detected in the RXM, it did not contribute to AhR-agonist activity. Instead, fractions containing the trimers LTr1 and 5,6,11,12,17,18-hexahydrocyclonona[1,2-b:4,5-b’:7,8-b’’]tri-indole (CTr), as well as some unidentified compounds showed the highest AhR activation. The fraction, containing the linear trimer LTr1, showed a weak anti-androgenic activity which has not been reported before. The study demonstrates the importance of a bioassay directed approach for identifying compounds that contribute most to the effects of mixtures.

中文翻译：

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吲哚-3-甲醇的酸缩合产物及其体外（抗）雌激素、（抗）雄激素和芳烃受体活性

摘要 本研究的目的是研究吲哚-3-甲醇酸缩合产物混合物（称为 RXM）的（抗）雌激素、（抗）雄激素和芳烃受体 (AhR) 激动活性，并鉴定这些化合物。最负责观察到的效果，使用体外受体报告基因转录激活生物测定。为此，制备并测试了 RXM 的 HPLC 级分。LC-MS/MS 分析用于鉴定一些酸缩合产物。RXM 显示出弱的雌激素和抗雄激素，以及强的 AhR 激动特性。含有 3,3-二吲哚基甲烷 (DIM) 的部分显示出较弱的雌激素和相对较强的抗雄激素活性。DIM 被证实是雄激素受体 (hAR) 拮抗剂和部分雌激素受体 (hERα) 激动剂。含有三聚体 [2-(indol-3-ylmethyl)indol-3-yl]indol-3-ylmethane (LTr1) 的部分也显示出抗雄激素活性。首次表明，DIM 不仅具有雌激素和抗雄激素作用，而且还具有抗雌激素作用。尽管吲哚 [3,2-b] 咔唑 (ICZ) 是一种有效的 AhR 激活剂并在 RXM 中检测到，但它对 AhR 激动剂活性没有贡献。取而代之的是，含有三聚体 LTr1 和 5,6,11,12,17,18-hexahydrocyclonona[1,2-b:4,5-b':7,8-b'']tri-indole (CTr) 的馏分，以及一些未鉴定的化合物显示出最高的 AhR 激活。含有线性三聚体 LTr1 的级分显示​​出以前从未报道过的弱抗雄激素活性。