芳基烃受体(AhR),一种配体激活的转录因子,被认为在体内介导许多生理作用,正在成为开发新疗法的目标。然而,先前的研究表明,AhR配体的下游效应不能仅仅基于配体作为激动剂或拮抗剂来预测,AhR信号的持久性被认为是关键的决定特征.本研究调查了从新西兰红藻中分离出的四种卤代吲哚的AhR活性,胡桃木:4,7-二溴-2,3-二氯吲哚(4DBDCI),7-溴-2,3-二氯-6-碘吲哚(BDCII),6,7-二溴-2,3-二氯吲哚(6DBDCI)和2,6,7-三溴-3-氯吲哚(TBCI)。它们激活AhR信号的能力,通过乙氧基间苯二酚O-脱乙基酶(EROD)测定法测量为CYP1A1活性,在人HepG2、小鼠Hepa1c1c7和大鼠H4IIE肝癌细胞中测定。四种化合物均诱导HepG2细胞CYP1A1活性,表明他们都是AhR的痛苦者。4DBDCI特别有效,诱导11倍的增加。Hepa1c1c7和H4IIE细胞,然而,通常对卤化吲哚反应较少。所有四种化合物都是持久的AhR激动剂,72h后诱导CYP1A1活性峰值。此外,2,3,6,7-取代的BDCII,6DBDCI和TBCI,而不是4DBDCI,与2,3,7,8-四氯二苯并-对二恶英(TCDD)竞争AhR结合,如通过抑制TCDD诱导的CYP1A1活性所观察到的。总的来说,目前的研究已经表征了四个以前未经测试的AhR配体,强调物种敏感性和信号持久性的差异,为它们未来的潜在用途提供一个框架。
The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor thought to mediate a number of physiological roles in the body, is becoming a target of interest for the development of new therapeutics. However, previous research has demonstrated that the downstream effects of AhR ligands cannot be predicted based simply on whether a ligand acts as an agonist or antagonist and the persistence of AhR signaling is thought to be a key determining feature. The current study investigated the AhR activity of four halogenated indoles isolated from the New Zealand red alga, Rhodophyllis membranacea: 4,7-dibromo-2,3-dichloroindole (4DBDCI), 7-bromo-2,3-dichloro-6-iodoindole (BDCII), 6,7-dibromo-2,3-dichloroindole (6DBDCI) and 2,6,7-tribromo-3-chloroindole (TBCI). Their ability to activate AhR signaling, measured as CYP1A1 activity via the ethoxyresorufin O-deethylase (EROD) assay, was determined in human HepG2, mouse Hepa1c1c7 and rat H4IIE liver cancer cells. All four compounds induced CYP1A1 activity in HepG2 cells, suggesting they all acted as AhR agonizts. 4DBDCI was particularly efficacious, inducing an 11-fold increase. Hepa1c1c7 and H4IIE cells, however, were generally less responsive to the halogenated indoles. All four compounds were persistent AhR agonizts, inducing peak CYP1A1 activity after 72 h. Moreover, the 2,3,6,7-substituted BDCII, 6DBDCI and TBCI, but not 4DBDCI, competed with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for AhR binding as observed by the inhibition of TCDD-induced CYP1A1 activity. Overall, the current study has characterized four previously untested AhR ligands, highlighting differences in species sensitivity and persistence of signaling to provide a framework for their potential future use.