Aromatic hydrocarbon receptor AHR

Antiproliferative compounds are easily detected using cell line or colonyforming unit (CPU) assays. Some of the potential mechanisms of non-antipro-liferative compounds leading to bone marrow toxicity include mitochondrial dysfunction [5, 6], aromatic hydrocarbon receptor (AhR) activation, receptor-mediated, altered receptor expression [7] and reactive intermediates [8, 9], but this list may grow with additional research as the mechanism(s) leading to bone marrow toxicity is still unknown for many compounds and will require significant amount of effort to elucidate. The next paragraphs briefly describe these potential mechanisms. 

Perhaps the best understood example of induction involves induction of the aromatic hydrocarbon receptor (AhR) by compounds such as TCDD and 3-methylcholanthrene. The use of suitable inhibitors of RNA and DNA polymerase activity has shown that inhibitors of RNA synthesis such as actinomycin D and mercapto(pyridethyl)benzimida-zole block aryl hydrocarbon hydroxylase induction, whereas hydroxyurea, at levels that completely block the incorporation of thymidine into DNA, has no effect. Thus it appears that the inductive effect is at the level of transcription and that DNA synthesis is not required. 

As observed in mammalian models, the immune system of fishes is a sensitive target organ system to evaluate toxicity. For a more thorough review of environmental immunotoxicology in fishes, with reference to specific classes of xenobiotics, readers are referred to several reviews that deal with the subject over a span of nearly three decades [45-47, 54-57], While fish in the environment may be exposed to a variety of xenobiotics, the most frequently investigated xenobiotics are the polycyclic aromatic hydrocarbons (PAHs) and halogenated aromatic hydrocarbons (HAHs) due to the presence and activation of the aryl hydrocarbon receptor (AhR) in fish, and heavy metals due to their ubiquitous environmental distribution. 

Abbreviations. AhR, aromatic hydrocarbon receptor TCDD, tetrachlorodibenzodioxin PXR, pregnenolone-16a-nitrile-X-receptor PCN, pregnenolone-16a-nitrile CAR, constitutive androstane receptor MC, methylcholanthrene PPARa, peroxisome proliferated-activated receptor-a FXR, famesoid-X-receptor LXR, liver-X-receptor RXR, retinod-X-receptor 5-HETE, 5-OH-eicosatetraenoic acid LTB4, leukotriene B4 13-HODE, hydroxyoctadecadienoic acid DMXAA, dimethylxan-thenone-4-acetic acid. 

Billard, S.M., M.E. Hahn, D.G. Franks, R.E. Peterson, N.C. Bols and P.V. Hodson. Binding of polycyclic aromatic hydrocarbons (PAHs) to teleost aryl hydrocarbon receptors (AHRs). Comp. Biochem. Physiol. 133B 55-68, 2002. 

Most of the research on xenobiotic receptors has been conducted in mammalian systems. These studies have identified three families of proteins as having important roles in regulating the response to xenobiotic chemicals (Table 1). The aryl hydrocarbon receptor (AHR), a member of the basic helix-loop-helix Per-ARNT-Sim (bHLH-PAS) family of transcription factors, is well known for its role in the altered gene expression and toxicity elicited by chlorinated dioxins and related planar halogenated aromatic hydrocarbons (PHAHs) as well as certain polynuclear aromatic hydrocarbons (PAHs)114 188 244. Several members of the nuclear/steroid... 

AhR activators in humans (aromatic hydrocarbon receptor)-tetrachlorodibenzodioxin (TCDD), (3-naphthoflavone, 3-methylcloranthrene. 

ClPAHs may be toxic to humans, and they have an equally important impact on the environment because several ClPAHs have also been found to exhibit mutagenic activity in Salmonella typhimurium in the Ames assay [229], To comprehensively estimate reactivity-activity for representative ClPAHs (see Fig. 6) on human and environmental species, Table 5 presents the ethoxyresorufin-O-deethylase (EROD) activities for binding substrates of chlorinated polycyclic aromatic hydrocarbons (ClPAHs) with aryl hydrocarbon receptors (AhRs) in the cytochrome... 

Ah receptor (AHR) A protein coded for by a gene of the Ah locus. The initial location of the Ah receptor is believed to be in the cytosol and, after binding to a ligand such as TCDD, is transported to the nucleus. Binding of aromatic hydrocarbons to the Ah receptor of mice is a prerequisite for the induction of many xenobiotic metabolizing enzymes, as well as for two responses to TCDD epidermal hyperplasia and thymic atrophy. Ah-responsive mice have a high-affinity receptor, whereas the Ah-nonresponsive mice have a low-affinity receptor. 

Increased P450 synthesis requires enhanced transcription and translation. A cytoplasmic receptor (termed AhR) for polycyclic aromatic hydrocarbons (eg, benzo[a]pyrene, dioxin) has been identified, and the translocation of the inducer-receptor complex into the nucleus and subsequent activation of regulatory elements of genes have been documented. A pregnane X receptor (PXR), a member of the steroid-retinoid-thyroid hormone receptor family, has recently been shown to mediate CYP3 A induction by various chemicals (dexamethasone, rifampin) in the liver and intestinal mucosa. A similar receptor, the constitutive androstane receptor (CAR) has been identified for the phenobarbital class of inducers (Sueyoshi, 2001 Willson, 2002). 

Abbreviations used in text AA, arachidonic acid AhR, aryl hydrocarbon receptor Amt, AhR nuclear translocator BR, bilirubin BV, biliverdin CYP1A1, cytochrome P4501A1 DRE, dioxin responsive element FICZ, 6-formylindolo(3,2b)carbazole HAH, halogenated aromatic hydrocarbon I3C, indole 3-carbinol ICZ, indolo-(3,2,-b)-carbazole PAH, polycyclic aromatic hydrocarbon RAR, retinoic acid receptor TCDD, 2,3,7,8-tetrachlorodi benzo-/>-dioxin Trp, tryptophan UGT 01, UDP-glucuronosy 1 transferase 01... 

The PAS domain transcriptional factor AhR is a nonnuclear receptor xenobiotic receptor. In the early 1990s, the AhR and its partner Ah receptor nuclear translocator (Arnt) protein were identified as a transcriptional sensor mediating the induction of CYP1A and 1B1 genes by dioxin and related polycyclic aromatic hydrocarbons [62, 63],... 

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