Dioxins/TCDD metabolism

An environmental protocol has been developed to assess the significance of newly discovered hazardous substances that might enter soil, water, and the food chain. Using established laboratory procedures and C-labeled 2,3,7,8-tetra-chlorodibenzo-p-dioxin (TCDD), gas chromatography, and mass spectrometry, we determined mobility of TCDD by soil TLC in five soils, rate and amount of plant uptake in oats and soybeans, photodecomposition rate and nature of the products, persistence in two soils at 1,10, and 100 ppm, and metabolism rate in soils. We found that TCDD is immobile in soils, not readily taken up by plants, subject to photodecomposition, persistent in soils, and slowly degraded in soils to polar metabolites. Subsequent studies revealed that the environmental contamination by TCDD is extremely small and not detectable in biological samples. 

Kociba, R.J. and B.A. Schwetz. 1982a. Toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Drug Metabol. Rev. 13 387-406. 

Koshakji, R.P., R.D. Harbison, and M.T. Bush. 1984. Studies on the metabolic fate of [14C]2,3,7,8-tetrachlo-rodibenzo-p-dioxin (TCDD) in the mouse. Toxicol. Appl. Pharmacol. 73 69-77. 

Pohl, R.J., M.O. James, J.R. Fouts, and J.R. Bend. 1976. Xenobiotic metabolism in marine fish treated with 2,3,7,8 - to traeh Iorodibenzo-p-dioxin (TCDD), 3-methylcholanthrene (3-MC), or 1,2,3,4-dibenzanthracene (DBA). Pharmacologist 18 207. 

Olson, J.R., T.A. Gasiewicz, and R.A. Neal. 1980b. Tissue distribution, excretion, and metabolism of 2,3,7,8-tetrachlorodibenzo-/ -dioxin (TCDD) in the golden Syrian hamster. Toxicol. Appl. Pharmacol. 56 78-85. 

Environmental chemicals and pollutants are also capable of inducing P450 enzymes. As previously noted, exposure to benzo[a]pyrene and other polycyclic aromatic hydrocarbons, which are present in tobacco smoke, charcoal-broiled meat, and other organic pyrolysis products, is known to induce CYP1A enzymes and to alter the rates of drug metabolism. Other environmental chemicals known to induce specific P450s include the polychlorinated biphenyls (PCBs), which were once used widely in industry as insulating materials and plasticizers, and 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin, TCDD), a trace byproduct of the chemical synthesis of the defoliant 2,4,5-T (see Chapter 56). 

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. 

Shiverick KT, Muther TF. 1983. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) effects on hepatic microsomal steroid metabolism and serum estradiol of pregnant rats. Biochem Pharmacol 32 991-995. 

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... 

Changes in steroid hormone metabolism in rat liver microsomes following administration of 2,3,7,8-tetrachlorodibenzo-p-dioxine (TCDD). Biochem. Pharmacol. 28, 497-9. 

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