Comparison of 2,3,7,8-tetrachlorodibenzo-p-dioxin, a potent inducer of aryl hydrocarbon hydroxylase, with 3-methylcholanthrene.
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Biomedical subjects
Publications and source records attributed to E Glover.
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2,3,7,8-Tetrachlorodibenzo-p-dioxin, a toxic contaminant frequently formed during the synthesis of the herbicide 2,4,5-trichlorophenoxyacetic acid, was shown to be a potent inducer of hepatic delta-aminolevulinic acid synthetase in the chick embryo. As little as 4.66 x 10(-12) mole of the contaminant per egg produces a significant increase in the activity of the enzyme. Induction of the enzyme is related to the dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin and, in contrast to that produced with other drugs, is prolonged in time, with 70 percent of the maximum induced activity present 5 days after a single dose. This contaminant is implicated as the likely causative agent in an outbreak of porphyria cutanea tarda in workers in a factory where 2,4,5-trichlorophenoxyacetic acid was being synthesized.
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A series of halodibenzo-p-dioxins bearing the arylazide photolabile functional group were synthesized and tested as photoaffinity labels for the Ah receptor. 2-Azido-3-iodo-7,8-dibromodibenzo-p-dioxin (KD = 0.76 X 10(-9) M) was selected for radiosynthesis. Analysis of the 125I-photoaffinity-labelled proteins in mouse-liver cytosol by denaturing gel electrophoresis revealed two peptides which had apparent molecular masses of 95,000 and 70,000 daltons respectively, were labelled in an approximately 1:1 ratio and were selectively labelled at low concentrations of the photoaffinity ligand (0.05 KD = 0.04 X 10(-9) M). In addition, their labelling was inhibited by co-incubation with an excess of unlabelled ligand. On chromatographic separation under non-denaturing conditions, these two peptides co-migrated. These studies suggest that the Ah receptor in mouse liver cytosol is a heterodimer composed of two non-covalently bound peptides (95 K and 70 K) which each have a ligand binding site.