p, p′-DDE and HCB: Mechanisms of Toxicity to Fetal and Embryonic Mammalian Cells
Rajesh K. Naz in Endocrine Disruptors, 2004
Although the toxic effects of HCB (and other dioxin-like chemicals) have been mainly ascribed to direct interaction with the aryl hydrocarbon receptor (AhR),50,59 mechanisms of action and subsequent effects of HCB or individual metabolites within the cell are areas of intense investigation. The cytochrome p450 pathway is the primary pathway by which most organic pollutants are targeted for elimination. Indeed, HCB appears to be targeted to cytochrome p450 pathways for xenobiotic transformation within several different tissues. Generally, persistent organic pollutants such as HCB are transformed to polar derivatives to allow for better urinary elimination. Polar derivatives have increased solubility in the aqueous cellular environment and removal through the urinary tract can be accomplished more readily. However, reactive oxygen species during metabolism is responsible for increased cellular oxidative stress and is a mechanism of toxicity for many chemicals that become bioactivated by this route.
The Role of Light and Electromagnetic Fields in Maintaining Vascular Health
Aruna Bakhru in Nutrition and Integrative Medicine, 2018
In response to both visible light and UV light, tryptophan is converted to 6-formylindolo[3,2-b]carbazole (FICZ). FICZ is the most likely endogenous activator of the aryl hydrocarbon receptor. This receptor induces the expression of multiple cytochrome P450 (CYP) enzymes in the liver that are essential for degrading xenobiotics [36]. Intriguingly, the aryl hydrocarbon receptor has been considered to be promiscuous in its response to multiple xenobiotics, including clinical drugs, food additives, industrial compounds, pesticides, and metals. However, it is likely that these all act indirectly by inhibiting the metabolism of FICZ through CYP hydroxylation and subsequent sulfation [37]. The receptor responds to FICZ at extremely low concentrations, and, if FICZ cannot be metabolized, the receptor will continue to induce CYP enzyme expression until successful clearance of the offending xenobiotic.
Neuroendocrine disease
Philip E. Harris, Pierre-Marc G. Bouloux in Endocrinology in Clinical Practice, 2014
These tumors are generally sporadic, but they may occur as a result of an underlying genetic defect, as in MEN1115 (see Chapter 9), FIPA53 (see Chapter 2), Carney complex (usually microadenomas),116 and MAS.113,114 They are most frequently seen in young adults. It has recently been demonstrated that the aryl hydrocarbon receptor–interacting protein (AIP) mutations seen in some FIPA patients also occur in sporadic tumors.190 These tumors are often sparsely granulated with a dotlike keratin pattern. There are no predictive molecular markers. They characteristically have a poor response to SS analogs. Pegvisomant can usually provide biochemical control. Radiotherapy may be necessary to control tumor growth.
Enhanced nuclear translocation and activation of aryl hydrocarbon receptor (AhR) in THP-1 monocytic cell line by a novel niosomal formulation of indole-3-carbinol
Published in Journal of Liposome Research, 2020
Neda Abbaspour Sani, Mahsa Hasani, Anvarsadat Kianmehr, Saeed Mohammadi, Mehdi Sheikh Arabi, Yaghoub Yazdani
Aryl hydrocarbon receptor (AhR) is a ligand-activated cytosolic receptor and transcription factor (Tibbitt et al.2016) which is normally expressed by epithelial and immune cells such as macrophages. AhR is mainly responsible for detoxification of environmental pollutants and metabolizing drugs (Micka et al.1997, Celius and Matthews 2010). However, any compound with polycyclic aromatic hydrocarbon (PAH) structure could serve as a ligand with variable affinities to AhR molecule. Therefore, AhR is believed to be involved in several cellular functions such as cell cycle regulation (Faust et al.2013) and immune response (Stockinger et al.2014). Regarding these multiple functions, it has been considered as a therapeutic target for several disorders including malignancies (either hematologic or solid tumours) and inflammatory disorders such as autoimmune diseases (Uyttenhove and Van Snick 2006, Veldhoen et al.2008).
The Effects of Astaxanthin on Proliferation and Differentiation of MG-63 Osteosarcoma Cells via Aryl Hydrocarbon Receptor (AhR) Pathway: A Comparison with AhR Endogenous Ligand
Published in Nutrition and Cancer, 2020
Nima Montazeri-Najafabady, Mohammad Hossein Dabbaghmanesh, Nazanin Chatrabnous, Mohammad Reza Arabnezhad
AST is a potent inducer of cytochrome P450 (CYP) 1A1 activity in rats and mice In Vivo. CYP1A1 has a critical role in metabolizing the drugs and chemicals, and also the synthesis and degradation of endogenous substances. The transcription of CYP1A1 is regulated through the aryl hydrocarbon receptor (AhR) (14). The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and it belongs to the Per-ARNT-Sim superfamily of proteins. AhR ligands elicit toxic responses such as endocrine disruption, tumor promotion, immunosuppression, and interference with the fatty acid metabolism and cell differentiation (15). Upon binding of a ligand to AhR, AhR is translocated to the nucleus in which it binds to Ah receptor nuclear translocator (ARNT) and forms an AhR/ARNT complex. After that, AhR/ARNT binds to the xenobiotic responsive element (XRE) in the promoter region of the target genes, such as CYP1A1 (14).
Lipidomics reveal aryl hydrocarbon receptor (Ahr)-regulated lipid metabolic pathway in alpha-naphthyl isothiocyanate (ANIT)-induced intrahepatic cholestasis
Published in Xenobiotica, 2019
Bao-Long Wang, Chang-Wen Zhang, Liang Wang, Kun-Long Tang, Naoki Tanaka, Frank J. Gonzalez, Yong Xu, Zhong-Ze Fang
Aryl hydrocarbon receptor (Ahr), a basic-helix-loop-helix (bHLH) Per-Arnt-Sim transcription factor, has been well known for its key role in xenobiotic-induced toxicity and carcinogenesis (Barouki et al., 2007). Ahr has been regarded as a key player in different liver toxicity model. The Ahr-null mice can exert resistant to a variety of TCDD-induced liver toxicity (Matsubara et al., 2012). Ahr activation can significantly enhance the liver damage induced in bile duct-ligated mice (Ozeki et al., 2011). To date, the Ahr’s role in ANIT-induced liver damage has just been investigated in see-through medaka which is a wildly used fish model, and the results indicated that Ahr agonist partially protected against acute hepatobiliary alteration in this model (Volz et al., 2008). However, the role of Ahr for ANIT toxicity remains unclear in rodents which are the common and suitable models for investigation of disease, toxicity, and drug therapy for human.
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