Metabolism of TCDD

Metabolism of TCDD. No metabolites of TCDD have been identified so far. It has recently been reported by Guenthner et al.(20) that TCDD can be metabolized by the mouse liver cytochrome P-U50 system to reactive intermediates, which easily bind covalently to cullular proteins. It is suggested that this extreme reactivity inhibits the formation of normal metabolites like phenols, dihydrodiols, or conjugated products. ... 

Huetter R, Philippi M. 1982. Studies on microbial metabolism of TCDD under laboratory conditions. Pergamon Ser Environ Sci 5 87-93. 

Poiger H, Schlatter C. 1985. Influence of phenobarbital and TCDD on the hepatic metabolism of TCDD in the dog. Experientia 41 376-378. 

Huetter R, Philippi M (1982), in Chlorinated Dioxins and Related Compounds Impact on the Environment..Studies on microbial metabolism of TCDD under laboratory conditions, p. 87-95, Eds Hutzinger O, Frei R, Merian E, Pocchiari F Pergamon Press, Oxford... 

Details of some inducible P450 forms that play key roles in the metabolism of xenobiotics are shown in Table 2.4. P450s belonging to family lA are induced by various lipophilic planar compounds including PAHs, coplanar PCBs, TCDD and other dioxins, and beta naphthoflavone (Monod 1997). As noted earlier, such planar compounds are also substrates for P450 lA. In many cases, the compounds induce the enzymes that will catalyze their own metabolism. Exceptions are refractory compounds such as 2,3,7,8-TCDD, which is a powerful inducer for P450 lA but a poor substrate. 

The results do not differentiate between C activity derived from TCDD and that of possible metabolites. However, small amounts of C activity were detected in the expired air and urine within the first 10 days following administration. This is evidence that some metabolic alteration or breakdown of TCDD occurs. 

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. 

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

Whether a toxin is naturally reactive to biological macromolecules or receptors, or requires metabolic activation to produce such a species, e.g. the enzyme-mediated transformation of tremorine (9) to the active parasympathomimetic agent oxotremorine (10), it will usually be subject to chemical or enzymic inactivation in vivo. Interruption of the latter process via appropriate substitution may thus lead to an increase in biological activity or toxicity over that of the parent compound. Perhaps the most striking example of this is provided by the extreme metabolic stability and toxicity of TCDD and the nontoxicity of its de- chloro analogue dibenzodioxin (Table 3). 

In theory, an isosteric/isoelectronic aromatic ring replacement within a toxic or therapeutic molecule should lead to a retention of biological activity. The fact that this is sometimes not observed may mean either that the activity is heterocycle-specific or that unforseen changes in metabolism, biological distribution and excretion, partition coefficient or stability have accompanied the molecular change. In such cases, activity may be observed in in vitro assays while not being observed in vivo (cf. the possible case of the dithiin analogue of TCDD in Table 3). 

A caveat with this approach is the potential for variability in elimination rate. The biologic half-life of TCDD has been estimated at 3-27 years in people chronically exposed to TCDD central-tendency half-lives are reported as 5.8-8.7 years in various studies (Pirkle et al. 1989 Michalek et al. 1996 Ott and Zober 1996). At least some of the variability is due to different sizes of the body lipid compartment and to variable activity of the CYP1A family to metabolize TCDD (EPA 2003). In fact, there is some... 

DA Bell NIEHS Explore genetic variability in the metabolism of carcinogens such as 2,3,7,8-TCDD ... 

It has been suggested that the potential for biological degradation of 2,3,7,8-TCDD in a wide variety of environmental samples is low (Arthur and Frea 1989). The fate of 2,3,7,8-TCDD in sediment and water from two lakes in Wisconsin was examined (Ward and Matsumura 1978). After incubation periods of up to 589 days, little metabolism of 2,3,7,8-TCDD was detected. The slight metabolism that was detected was stimulated by the presence of sediment and the addition of nutrients (Ward and Matsumura 1978). Also, 2,3,7,8-TCDD does not hydrolyze in water (Mabey et al. 1982 Miller et al. 1987). 

Poiger H, Weber H, Schlatter CH. 1982. Special aspects of metabolism and kinetics ofTCDD in dogs and rats Assessment of toxicity of TCDD-metabolites(s) in guinea pigs. In Hutzinger O, Frei RW, Merian E, et al., eds. Chlorinated dioxins and related compounds Impact on the environment. New York, NY Pergamon Press, 317-325. 

Unkila M, Pohjanvirta R, MacDonald E, et al. 1993 a. Differential effect of TCDD on brain serotonin metabolism in a TCDD-susceptible and a TCDD-resistant rat strain. Chemosphere 27(l-3) 401-6. 

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