Ligand metabolism and transport - Aryl hydrocarbon receptor
6 important questions on Ligand metabolism and transport - Aryl hydrocarbon receptor
Name some chracteristics of the AhR (3).
Target genes, ligands and family.
- Belongs to bHLH/PAS family of transcription factors (like nuclear receptors)
- Dioxin is a ligand. Exogenous ligands: 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) , but also halogenated and polyaromatic hydrocarbons
- Target genes: CYP genes + Others in xenobiotic handling: NQO1*, GSTA2, UGT1A1, Nrf2
What are consequences of activating the AhR?
- Hepatotoxicity
- Tumour promotion
- Endocrine disruption
- Tissue wasting
- Immune system dysfunction
Explain the full pathway of AhR receptor.
- An inactive form of the AHR is cytoplasmic and complexed with HSP90, AIP and SRC.
- Upon ligand binding, the AHR complex translocates to the nucleus, where the AHR forms a complex with ARNT
- Binds to XRE (Xenobiotic response element), inducing AHR-target gene expression. XRE are DNA sequences in the upstream region of certain genes. -> triggers transcription of genes.
- AHRR competes with the AHR for binding with ARNT and forms the inactive heterodimer AHRR-ARNT. The dissociation of the AHR transcriptional complex leads to translocation of the AHR to the cytoplasm, where it is degraded via the proteasomal pathway.
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We primarily know the AhR from toxicity. What do we know about the physiology role?
- AHR exerts a major influence in modulating a wide spectrum of cytokine expression and immune cell differentiation and functions
- it plays essential roles in development, normal organ functions, and metabolic homeostasis in human
Why do dioxin (2,3,7,8-Tetrachlorodibenzodioxin) and benzoapyrene exist?
- Dioxin (2,3,7,8-Tetrachlorodibenzodioxin): side product form organic synthesis and burning of organic material
- Polycyclic aromatic hydrocarbon: incomplete combustion of organic matter.
- Cigarette smoke: Diol epoxide metabolites are carcinogens.
What is auto-inductie van toxische enzymen?
- Benzo(a)pyreen
- CYP1A1 zet BaP om in diol-epoxiden, die covalent aan DNA binden → mutaties → carcinogenese.
- Hetzelfde enzym dat bedoeld is om BaP te detoxificeren, maakt het eigenlijk toxischer.
- CYP1A1 zet BaP om in diol-epoxiden, die covalent aan DNA binden → mutaties → carcinogenese.
- Dioxinen
- CYP1A1/CYP1B1 proberen TCDD te metaboliseren, maar dit gebeurt zeer langzaam.
- Hierdoor ontstaat een constante AhR-activatie, wat leidt tot oxidatieve stress, ontsteking, immunotoxiciteit en teratogenese.
- De “detoxificatiepoging” versterkt dus indirect de toxische effecten.
- CYP1A1/CYP1B1 proberen TCDD te metaboliseren, maar dit gebeurt zeer langzaam.
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