2,3,7,8-Tetrachlorodibenzo-p-dioxin: environmental contaminant and molecular probe.
The chlorinated dibenzo-p-dioxins and dibenzofurans are formed as trace contaminants during the synthesis of a number of commercially important chemicals. The prototype compound of this group, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), is one of the most potent low molecular weight toxins and teratogens known, and its inadvertent dispersion in the environment has caused concern about the potential hazard to human health. In studying the biochemical effects of TCDD, it was found to be extraordinarily potent as an inducer of two hepatic enzymes: 1) delta-aminolevulinic acid synthetase, the initial and rate-limiting enzyme in heme synthesis, and 2) aryl hydrocarbon hydroxylase, a cytochrome P-450-mediated microsomal monooxygenase. Among a series of halogenated dibenzo-p-dioxins there is an excellent correlation between their toxic potency and their potency as inducers of these two enzymes. The administration of polycyclic aromatic hydrocarbons (e.g., 3-methylcholanthrene (MC)) to certain inbred strains of mice induces aryl hydrocarbon hydroxylase, while other inbred strains fail to respond; and the trait of aryl hydrocarbon responsiveness is inherited as an autosomal dominant. TCDD, about 30,000 times as potent as MC, induces all strains whether responsive or nonresponsive to MC; however, the responsive strains are more sensitive (ED 50 approximately 1 X 10(-9) mole/kg) to TCDD than are the nonresponsive strains (ED50 larger than or equal to 1 X 10(-8) mole/kg). The results suggest that the mutation in the nonresponsive strains results in a ligand binding site (an induction receptor) that has a diminished affinity for MC and TCDD. The correlation among the halogenated dibenzo-p-dioxins, between their potency as toxins and their potency as inducers of aryl hydrocarbon hydroxylase, is discussed in relationship to various proposed mechanisms of toxicity.
D000624:5-Aminolevulinate Synthetase / Q000378:metabolism; D000152:Acne Vulgaris / Q000139:chemically induced; D000345:Affinity Labels; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D002642:Chick Embryo; D002645:Chickens; D004147:Dioxins / Q000506:poisoning*; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced; D004787:Environmental Pollution; D006801:Humans; D007220:Industrial Waste; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008968:Molecular Conformation; D000072317:Polychlorinated Dibenzodioxins / Q000378:metabolism / Q000494:pharmacology / Q000506:poisoning*; D013723:Teratogens
D000345:Affinity Labels; D004147:Dioxins; D007220:Industrial Waste; D000072317:Polychlorinated Dibenzodioxins; D013723:Teratogens; D001189:Aryl Hydrocarbon Hydroxylases; D000624:5-Aminolevulinate Synthetase