The Ah Receptor: A Specific Site for Action of Chlorinated Dioxins?
The Ah receptor is a major regulatory gene product of the Ah gene complex. Its best-known function is regulation of the induction of cytochrome P1-450 (aryl hydrocarbon hydroxylase) and several associated drug-metabolizing enzyme activities. TCDD (2,3,7,8-tetra- chlorodibenzo-p-dioxin) and related halogenated aromatic compounds are high affinity ligands for the Ah receptor. Generally, those tissues with high concentrations of Ah receptor are the most susceptible to TCDD toxicity, but presence of the receptor, in itself, does not ensure that toxicity from halogenated aromatics will occur. Toxicity of various ligands (TCDD, other halogenated dibenzo-p- dioxins, halogenated dibenzofurans, polychlorinated biphenyls, poly- cyclic aromatic hydrocarbons) also generally is correlated with the affinity with which the specific chemical binds to Ah receptor. However, certain compounds such as 3-methylcholanthrene bind to Ah receptor with an affinity sililar to that of TCDD, yet are far less toxic in vivo. Thus binding affinity alone is not the sole determinant to toxicity. Overall, binding to Ah receptor appears to be an essential early step in the mechanism of toxicity of chlorinated dioxins and related compounds. Some subsequent receptor-regulated event(s) must be required for full expression of toxicity, but the specific nature of such events is unknown.
KeywordsSucrose Density Gradient Aryl Hydrocarbon Hydroxylase Scatchard Plot Analysis Hepatic Cytosol Peak Sedimenting
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