The role of receptors in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity.
There is good evidence that the Ah-(TCDD-) receptor plays a role in the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and its congeners. TCDD and other chlorinated aromatic hydrocarbons with chlorine atoms in lateral positions (2,3,7,8-tetrachlorodibenzofuran, 3,3',4,4'-tetrachloroazoxybenzene, 3,3',4,4'(5,5')-tetra(hexa)chlorobiphenyl), all bind to the receptor and show a similar pattern of toxicity, although there is a wide range in potency. The Ah-receptor is viewed as the major product of the regulatory gene of the Ah-locus in the mouse. Several of the toxicities of TCDD and congeners (teratogenesis, thymic involution and hepatic porphyria) have been shown to segregate with the Ah-locus. In vitro studies using keratinizing cells or fetal thymus organ culture have shown a good correlation between activity as ligands of the receptor and toxicity for the compounds discussed. The great differences in toxic potency of these compounds in vivo may therefore be a result of variation in rate of metabolism and excretion rather than differences in affinity for the Ah-receptor. The physiological role of the Ah-receptor is discussed, whether it has developed as a response to exposure to toxic substances in the environment, as a means of induction of P-450-dependent polysubstrate mono-oxygenase activities in order to make those substances more liable for excretion--or is there a physiological ligand? TCDD has a long half-life in the body, and a sustained competition for binding to the receptor between TCDD and a ligand of importance for normal cell functions may result in toxicities such as the wasting syndrome. This tentative ligand could be of varying importance in different species, which might explain the great variation in sensitivity between species, the hamster being about 5000 times less sensitive than the guinea pig.
D000014:Abnormalities, Drug-Induced / Q000209:etiology / Q000235:genetics; D000818:Animals; D005075:Biological Evolution; D001693:Biological Transport, Active; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury; D006224:Cricetinae; D003577:Cytochrome P-450 Enzyme System; D004147:Dioxins / Q000633:toxicity*; D004622:Embryo, Mammalian / Q000187:drug effects; D004790:Enzyme Induction; D005260:Female; D006168:Guinea Pigs; D006846:Hydrocarbons, Halogenated / Q000378:metabolism; D008107:Liver Diseases / Q000235:genetics; D008206:Lymphatic Diseases / Q000139:chemically induced / Q000235:genetics; D051379:Mice; D008812:Mice, Hairless; D008815:Mice, Inbred Strains / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D010105:Oxygenases / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000378:metabolism / Q000633:toxicity*; D011083:Polycyclic Compounds / Q000378:metabolism; D011164:Porphyrias / Q000139:chemically induced / Q000235:genetics; D011247:Pregnancy; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012871:Skin Diseases / Q000139:chemically induced / Q000235:genetics; D013329:Structure-Activity Relationship; D013950:Thymus Gland
D002273:Carcinogens; D004147:Dioxins; D006846:Hydrocarbons, Halogenated; D000072317:Polychlorinated Dibenzodioxins; D011083:Polycyclic Compounds; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases