Ah receptor complex

There are even receptors that are known to become activated only due to interaction with a synthetic chemical, and no physiological agonist for such a receptor has been characterized. A model receptor in this class is the so-called Ah receptor complex that becomes activated subsequent to its exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxiu (TCDD). Activation of the. Ah receptor... 

Denison MS, Fisher JM, Whitlock JP. 1989. Protein-DNA interactions at recognition sites for the dioxin-Ah receptor complex. J Biol Chem 264 16478-16482. 

PBPK models for 2,3,7,8-TCDD are discussed below. The pharmacokinetic behavior of 2,3,7,8-TCDD, especially distribution, has been shown to be dose-dependent and involves protein binding and enzyme induction in hepatic tissue. Thus, terms describing these interactions have been included in the animal models described below. Furthermore, since induction of these dioxin-binding proteins is a process mediated by the interaction of a dioxin-receptor (the Ah receptor) complex with specific binding sites on DNA additional terms were included in the models. For a detailed explanation regarding the Ah receptor and its involvement in the mechanism of action of 2,3,7,8-TCDD and structurally related halogenated aromatic hydrocarbons, see Section 2.4.2. 

Enan E, Matsumura F. 1996. Identification of c-src as the integral component of the cytosolic Ah receptor complex, transducing the signal of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) through the protein phosphorylation pathway. Biochem Pharmacol 52 1599-1612. 

Denison, M.S., Fisher, J.M., and Whitlock, ).P. Jr. (1988) The DNA recognition site for the dioxin-Ah receptor complex. Nucleotide sequence and functional analysis./. Biol. Chem., 263,17221-17224. 

Nuclear Receptor Regulation of Hepatic Cytochrome P450 Enzymes. Figure 1 General mechanism for transcriptional activation of CYP genes by xenochemicals that activate their cognate xeno-receptor proteins. In the case of Ah receptor, the receptor s heterodimerization partner is Arnt, whereas in the case of the nuclear receptors CAR, PXR, and PPARa, the heterodimerization partner is RXR. The coactivator and basal transcription factor complexes shown are each comprised of a large number of protein components. 

The toxicology of PCBs is complex and not fully understood. Coplanar PCBs interact with the Ah-receptor, with consequent induction of cytochrome P4501A1/2 and Ah-receptor-mediated toxicity. Induction of P4501A1 provides the basis of valuable biomarker assays, including bioassays such as CALUX. Certain PCBs, for example, 3,3, 4,4 -TCB, are converted to monohydroxymetabolites, which act as thyroxine antagonists. PCBs can also cause immunotoxicity (e.g., in seals). 

Coplanar PCBs, PCDDs, and PCDFs express Ah-receptor-mediated toxicity (Chapter 6, Section 6.2.4). Binding to the receptor leads to induction of cytochrome P4501 and a number of associated toxic effects. Again, toxic effects are related to the extent of binding to this receptor and appear to be additive, even with complex mixtures of planar polychlorinated compounds. Induction of P4501A1/2 has been widely used as the basis of a biomarker assay. Residue data can be used to estimate TEQs for dioxin (see Chapter 7, Section 7.2.4). 

Due to tlie likelihoods that (1) multiple mechanisms (Ah-receptor-dependent mechanisms, Ah-receptor independent mechanisms, or both) may be involved in health effects induced by PBBs/PBDEs, (2) different PBB/PBDE congeners may produce effects by different mechanisms, and (3) humans are exposed to complex mixtures of interacting PBBs/PBDEs with differing biological activities, as well as to the lack of a suitable approach for quantitatively evaluating joint toxic action from concurrent exposures to PBBs, PBDEs, PCBs, CDDs, and/or CDFs in tlie environment, data from commercial PBB and PBDE mixtures are used to develop MRLs for assessing health risks from environmental exposures to PBBs or PBDEs. 

Initial binding of a PBB congener to the Ah receptor is followed by an activation or transcription step and subsequent accumulation of occupied nuclear receptor complexes. These complexes interact with a specific DNA sequence in the CYPlAl gene (which regulates the expression of cytochrome P-450IA1... 

Figure 9.9 Interaction of the Ah-receptor-ligand complex with the 5 flanking region of the P450 1A1 gene. Two dioxin responsive elements (DREs) appear to lie approximately 1000 or more base pairs upstream from the 1A1 transcriptional s tart site. These elements appear to be transcriptional enhancers, whereas less direct evidence indicates an inhibitory element ( negative control element ) between 400 and 800 bases upstream. The negative control element may inhibit the 1A1 promoted although the conditions for this inhibition are, as yet, undefined. (Adapted from A. B. Okey, Pharmacol. Ther. 45 241-298, 1990.)...

Fig. 5.1 Principle behind the CALUX bioassay for Ah-receptor agonists. Following binding of the agonist to the Ah-receptor, the complex will be transported to the nucleus and bind to a so-called dioxin responsive element, resulting in the increased transcription of the luciferase gene and production of luciferase. Following incubation this enzyme can subsequently be measured in cell lysates by a light producing reaction.

A receptor-mediated PBPK model was developed by Andersen et al. (1993). The model included interactions of the Ah-TCDD complex with DNA and was used to examine the tissue disposition of... 

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