Proteins TCDD complex

More subtle modes of action are also possible since the response to hormone receptor binding is complex and could be affected by chemical interference with receptor-related proteins, DNA methylation or histone acetylation. Dioxin (TCDD), for example, reduces the ability of the oestrogen-receptor complex to bind to the oestrogen response element of DNA, reducing gene transcription. ... 

Figure 5.33 Mechanism of the receptor-mediated induction of CYP1A1 by a polycyclic hydrocarbon such as TCDD. The inducer-receptor (AhR) complex enters the nucleus, binds with ARNT, and the complex binds to the CYP1A1 gene in the DNA. This induces the production of CYP1A1 mRNA, which leads to the production of CYP1A1 protein and functional enzyme. Abbreviations AIP, AhR interacting protein AhR, aryl hydrocarbon receptor HSP, heat shock protein 90 ARNT, AhR nuclear translocator E.R., endoplasmic reticulum.

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. 

Figure 32.6. Model of AhR-mediated mechanism of action of TCDD and related HAHs. TCDD binds to the AhR in the cytoplasm. This complex interacts with another cytosolic protein (ARNT) and is translocated into the nucleus where it binds to specific DNA enhancer sequences upstream of TCDD responsive genes. Exactly which genes are important in the resulting immune suppression is unclear. Abbreviations AhR, aryl hydrocarbon receptor ARNT, AhR nuclear transporter DRE, dioxin-responsive elements.

---