Dioxins/TCDD enzyme induction

Ah receptor a protein, which binds polycyclic hydrocarbons such as dioxin (TCDD). Binding to this receptor is part of the process of induction of xenobiotic metabolizing enzymes. 

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. 

Hexachlorobenzene acted like a weak Ah receptor agonist and caused an up to 40% decrease in specific hepatic cytosol binding of 2,3,7,8-TCDD in rat cells (Hahn et al. 1989b). Similarly, 2,3,7,8-TCDD-induced myelotoxicity and enzyme induction was antagonized by 1-amino-3,7,8-trichlorodibenzo-p-dioxin in B6C3Fj mice presumably by competitive binding to the cytosolic Ah receptor (Luster et al. 1986). Comparable effects were observed in vitro in murine bone-marrow-cells cultures. Treatment of Fischer 344 rats orally with di(2-ethylhexyl)phthalate (DEHP) before or after oral administration of... 

Madsen C, Larsen JC. 1989. Relative toxicity of chlorinated dibenzo-para-dioxins, and dibenzofiirans measured by thymus weight and liver-enzyme induction in perinatally dosed rats 2,3,7,8-TCDD, 2,3,4,7,8-PCDF, 1,2,3,7,8-PCDD. Chemosphere 18 955-966. 

Many inducers are substrates for the enzymes that they induce. From a teleological perspective, the purpose of enzyme induction is to foster clearance of xenobiotic chemicals from the body (the dioxin, TCDD, is a notable exception to this generalization). TCDD is a potent inducer of many DMEs that are regulated by the AHR (Table 3) however, TCDD is highly resistant to metabolism by any of the enzymes that it induces, particularly in... 

Many of the toxic and biological effects induced by polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs) and PCBs such as carcinogenesis, reproductive disturbances and immunotoxic effects are believed to be mediated via the hepatic cytosolic aryl hydrocarbon receptor (Ah receptor) [254,255]. Based on in vitro and in vivo studies, the toxicity of individual organochlorines have been determined relative to 2,3,7,8-tetrachlorodibenzo-p -dioxin (TCDD) and expressed as toxic equivalency factors (TEFs) [254, 256]. In addition to PCDD/F, structurally related PCBs and PCNs bind to the Ah receptor. After binding to the Ah-receptor, the receptor-ligand complex is transferred into the nucleus where it binds to specific DNA sequences and causes transcription of structural genes, which in turn causes synthesis of various cytochrome P4501A1-dependent enzymes such as ethoxyresorufin O-deethylase (EROD) and aryl hydrocarbon hydroxylase (AHH). TEFs for PCNs have been estimated from enzyme-induction assays of EROD and AHH [10, 257] and Luciferase assays in rat cells [12] cf. Table 4. 

Chronic exposure to dioxins has resulted in splenic and testicular atrophy, elevated gamma-glutamyl transpeptidase levels, elevated cholesterol levels, and abnormal neurologic findings. Additional effects include enzyme induction, diabetes, and endocrine changes. The chronic, noncancer reference exposure level of 3.5 xl0 pgm is listed for TCDD or 2,3,7,8-equivalents by the California Air Pollution Control Officers Association Air Toxics Hot Spots Program. 

The evidence to date implies that the Ah receptor participates in every biological response to TCDD. For example, studies of stmeture activity relationships among congeners of TCDD reveal a correlation between a compound s specific binding affinity and its potency in eliciting biochemical responses, such as enzyme induction [171]. Furthermore, inbred mouse strains in which TCDD binds with lower affinity to the receptor exhibit decreased sensitivity to dioxin s biological effects, such as thymic involution, cleft palate formation, and hepatic porphyria. While there are a few... 

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