In vitro differential responses of rat and human aryl hydrocarbon receptor to two distinct ligands and to different polyphenols

Abstract

TCDD (2,3,7, and several other environment/food-borne toxic compounds induce their toxicity via the aryl hydrocarbon receptor (AhR). AhR is also modulated by various endogenous ligands e.g. highly potent tryptophan (Trp)-derivative FICZ (6-formylindolo[3,2-b]carbazole) and natural ligands abundant in the human diet e.g. polyphenols. Therefore, evaluating AhR species-specific responses is crucial for understanding AhR physiological functions, establishing risk assessments, and exploring the applicability of AhR mediators in drug and food industry towards human-based usages. We studied AhR transactivation of FICZ/TCDD in vitro in a time-dependent and species-specific manner using dioxin responsive luciferase reporter gene assays derived from rat (DR-H4IIE) and human (DR-HepG2) hepatoma cells. We observed for the first time that FICZ potency was similar in both cell lines and was 40 times higher than TCDD in DR-HepG2 cells. Depleting 2Trp-derivative endogenously produced ligands by using culture medium without Trp, resulted in 3-fold higher AhR activation upon adding FICZ in DR-H4IIE cells, in contrast to DR-HepG2 cells which revealed a fast degradation of FICZ induction from 10h post-exposure to complete disappearance after 24h. Seven polyphenols and a mixture thereof, chosen based on commercially recommended doses and adjusted to human realistic exposure, caused rat and human species-specific AhR responses. Two isoflavones (daidzein and genistein) induced rat AhR synergistic effects with FICZ and/or TCDD, while quercetin, chrysin, curcumin, resveratrol, and the mixture exerted a strong inhibitory effect on the human AhR. Strikingly, resveratrol and quercetin at their realistic nanomolar concentrations acted additively in the mixture to abolish human AhR activation induced by various TCDD concentrations. Taken together, these results illustrate the species-specific complexity of AhR transcriptional activities modulated by various ligands and highlight the need for studies of human-based approaches.

Involvement of the CYP1A1 inhibition-mediated activation of aryl hydrocarbon receptor in drug-induced hepatotoxicity

“…Some compounds are also reported to show species differences in CYP1A1 inhibition (Westerink et al, 2008;Watanabe et al, 2020). On the other hand, the AHR-activating potency of FICZ is reported to be similar in rats and humans (Doan et al, 2020), and the AHR response to exogenous ligands is generally considered to vary little between species. From these facts, it will be of great interest to further investigate whether a compound showing species differences in CYP1A1 inhibition may show species differences in hepatotoxicity caused by this mechanism.…”

Human Adult Microbiota in a Static Colon Model: AhR Transcriptional Activity at the Crossroads of Host–Microbe Interaction

“…Indeed, an exacerbated cellular response of AhR such as the one exerted by persistent organic pollutants, and particularly dioxinlike compounds, is associated with the triggering of toxicity pathways and affects the transcriptome in a distinct way [138]. Meanwhile, transient but commonly potent AhR activation is induced by endogenous ligands such as the well-studied tryptophan derivative FICZ [139]. This last one is probably the form of interaction of microbial metabolites with AhR due to the physiological machinery regulating their production and degradation in the biological context.…”

Editorial: Role of the Aryl Hydrocarbon Receptor in Immune Modulation

“…The aryl hydrocarbon receptor (AhR), originally discovered as a xenobiotic receptor involved in upregulating metabolic enzymes, has become increasingly linked to physiological processes (McMillan and Bradfield, 2007;Okey, 2007;Abel and Haarmann-Stemmann, 2010;Wang et al, 2017;Roman et al, 2018;Rothhammer and Quintana, 2019). The discovery of endogenous, dietary and bacterial-derived ligands for the AhR further supports its involvement in the homeostatic regulation of biological processes (Adachi et al, 2001;Denison et al, 2011;Bessede et al, 2014;Faber et al, 2018;Rannug and Rannug, 2018;Doan et al, 2020). Yet, dysregulation of many of these processes can lead to disease states involving the immune system.…”