ArticleProceedings of the National Academy of Sciences of the United States of America2012
Inhibition of cytochrome P4501-dependent clearance of the endogenous agonist FICZ as a mechanism for activation of the aryl hydrocarbon receptor.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 114 papers.
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Who cites it
114 citing papers in PubMed, 212 citations in OpenAlex.
- Cooperation or Conflict? Molecular and Physiological Cross-Talk Between the Aryl Hydrocarbon and Vitamin D Receptors.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Aryl hydrocarbon receptor pharmacology-mechanisms, ligands, and therapeutic potential.Pharmacological reviews · 2026Review
- CYP1A1 as a conserved metabolic circuit linking environmental sensing to immune regulation.Archives of toxicology · 2026Review
- Comparative 28-day mouse study of topically applied aryl hydrocarbon receptor ligands: microbiota-derived indoles, therapeutic tapinarof, pollutants 2,3,7,8-tetrachlorodibenzo-p-dioxin and diesel exhaust particles.Chemico-biological interactions · 2026Article
- The aryl hydrocarbon receptor: structure, signaling, physiology and pathology.Signal transduction and targeted therapy · 2026Review
- Article
- Systematic identification and characterization of regulators of aryl hydrocarbon receptor signaling.bioRxiv : the preprint server for biology · 2025Article
- The role of the AHR in host-pathogen interactions.Nature reviews. Immunology · 2025Review
- The Aryl Hydrocarbon Receptor (AHR): Peacekeeper of the Skin.International journal of molecular sciences · 2025Review
- Environmentally persistent free radicals lead to selective inhibition of CYP1 monooxygenase activities, and increased production of reactive oxygen species by reaction uncoupling.Frontiers in public health · 2025Article
- CYP1B1 knockout enhanced IFN-γ production is required but not sufficient for protection of cigarette smoke-exposed mice against lethal influenza virus infection.Frontiers in immunology · 2025Article
- Discovery of a novel AhR-CYP1A1 axis activator for mitigating inflammatory diseases using anActa pharmaceutica Sinica. B · 2025Article
- Aryl Hydrocarbon Receptor Alleviates Hepatic Fibrosis by Inducing Hepatic Stellate Cell Ferroptosis.Journal of cellular and molecular medicine · 2024Article
- The influence of AHR on immune and tissue biology.EMBO molecular medicine · 2024Review
- Article
- Differential cell type-specific function of the aryl hydrocarbon receptor and its repressor in diet-induced obesity and fibrosis.Molecular metabolism · 2024Article
- Light Sensing beyond Vision: Focusing on a Possible Role for the FICZ/AhR Complex in Skin Optotransduction.Cells · 2024Review
- Aryl Hydrocarbon Receptor Signalling in the Control of Gut Inflammation.International journal of molecular sciences · 2024Review
- Aryl hydrocarbon receptor and IL-13 signaling crosstalk in human keratinocytes and atopic dermatitis.Frontiers in allergy · 2024Article
- Next-generation of BBQ analogues that selectively target breast cancer.Frontiers in chemistry · 2024Article
54 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Altered systemic levels of 6-formylindolo[3,2-b]carbazole (FICZ), an enigmatic endogenous ligand for the aryl hydrocarbon receptor (AHR), may explain adverse physiological responses evoked by small natural and anthropogenic molecules as well as by oxidative stress and light. We demonstrate here that several different chemical compounds can inhibit the metabolism of FICZ, thereby disrupting the autoregulatory feedback control of cytochrome P4501 systems and other proteins whose expression is regulated by AHR. FICZ is both the most tightly bound endogenous agonist for the AHR and an ideal substrate for cytochrome CYP1A1/1A2 and 1B1, thereby also participating in an autoregulatory loop that keeps its own steady-state concentration low. At very low concentrations FICZ influences circadian rhythms, responses to UV light, homeostasis associated with pro- and anti-inflammatory processes, and genomic stability. Here, we demonstrate that, if its metabolic clearance is compromised, femtomolar background levels of this compound in cell-culture medium are sufficient to up-regulate CYP1A1 mRNA and enzyme activity. The oxidants UVB irradiation and hydrogen peroxide and the model AHR antagonist 3'-methoxy-4'-nitroflavone all inhibited induction of CYP1A1 enzyme activity by FICZ or 2,3,7,8-tetrachlorodibenzo-p-dioxin, thereby subsequently elevating intracellular levels of FICZ and activating AHR. Taken together, these findings support an indirect mechanism of AHR activation, indicating that AHR activation by molecules with low affinity actually may reflect inhibition of FICZ metabolism and raising questions about the reported promiscuity of the AHR. Accordingly, we propose that prolonged induction of AHR activity through inhibition of CYP1 disturbs feedback regulation of FICZ levels, with potential detrimental consequences.
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