Identification of metabolites of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) formed on incubation with isolated rat hepatocytes

Sawahata, Tadashi; Olson, James R.; Neal, Robert A.

doi:10.1016/s0006-291x(82)80050-8

Cited by 49 publications

(15 citation statements)

References 8 publications

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“…The primary in vivo metabolic products of TCDD seem to be phenols. Using rat heptocytes, Sawahata et al (73) were able to generate at least two metabolites of TCDD which were identified as 1-hydroxy-2,3,7,8-TCDD and 8-hydroxy-2,3,7-trichlorodibenzo-p-dioxin. Poiger et al (74) were able to identify five phenolic metabolites produced in vivo by dogs.…”

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confidence: 99%

The role of structure in the disposition of halogenated aromatic xenobiotics.

Birnbaum¹

1985

Environ Health Perspect

101

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Halogenated aromatic xenobiotics such as the chlorinated and brominated biphenyls, naphthalenes, dibenzodioxins, and dibenzofurans are widespread environmental contaminants. The number, position, and nature of the halogen atoms as well as the structure of the aromatic rings influence the disposition of these chemicals in living systems. Absorption is governed primarily by the physical properties of lipophilicity and solubility. Distribution through the blood occurs by nonspecific binding to plasma proteins and cellular components. Liver and adipose tissue are the major depots. Metabolism is a prerequisite for excretion. The highly substituted isomers tend to be resistant to metabolism. The route of excretion shifts from urine to feces with increasing size and number of halogen atoms. Although pharmacokinetic modeling has allowed some predictions to be made from one compound to another or across species, more information on metabolism is required in order to improve the ability to predict the disposition in humans of this class of toxic environmental pollutants.Halogenated aromatic hydrocarbons constitute a broad class of compounds with varying structure, uses, environmental occurrence, and toxicity. The nature of the halogen atoms(s) involved and the structure of the aromatic ring(s) deternines the physical properties of these molecules as well as influencing the response of biological systems to them. The availability of these compounds to their biological target site is governed by a complex interaction of physical and biological factors. In this paper, the structure of halogenated aromatic hydrocarbons will be correlated with their disposition in living systems. Since extensive reviews have been written on the less complex compounds, such as the halogenated benzenes, only the multiring structures such as the halogenated naphthalenes, biphenyls, dibenzodioxins, and dibenzofurans will be considered. Several recent reviews have concerned the pharmacokinetics of polyhalogenated aromatic hydrocarbons (1-4); 2,3,7,8-tetrachlorodibenzofuran (TCDF) (5); 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (6,7); and a comparison of dioxins and furans (8). I shall attempt to emphasize the similarities and differences in the disposition of these compounds as well as discuss the results of some current investigations both in our laboratory and others.There are 75 possible chlorinated dibenzodioxins and 135 chlorinated dibenzofuran isomers. The total number of chlorinated biphenyl and naphthalene isomers is in the hundreds. Most of these isomers exist in complex indus-

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confidence: 99%

The role of structure in the disposition of halogenated aromatic xenobiotics.

Birnbaum¹

1985

Environ Health Perspect

101

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“…Although metabolic transformation occurred very slowly, TCDD has been shown to be metabolized in vim and in vitro (30,31). The binding and subsequent slow metabolism of TCDD by cytochrome P-450d therefore remains a possibility, although we were never able to obtain evidence for metabolism by cytochrome P-450d in these experiments.…”

Section: Discussionmentioning

confidence: 80%

TCDD (2, 3, 7, 8‐tetrachlorodibenzo‐p‐dioxin) is a tight binding inhibitor of cytochrome p‐450D

Voorman

Aust

1989

J. Biochem. Toxicol.

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Based on data indicating that compounds which induce cytochrome P-450d also bind to the enzyme [R. Voorman and S. D. Aust (1987). Toxicol. Appl. Pharmacol. 90, 69-78], we investigated the inhibition of cytochrome P-450d-dependent estradiol 2-hydroxylase by (2,3,7,8-tetrachlorodibenzo-p-dioxin TCDD), using ligand-free cytochrome P-450d from isosafrole-treated rats. Since maximum inhibition of estradiol 2-hydroxylase occurred at TCDD concentrations comparable to the concentration of enzyme (50 nM), a modified form of steady-state kinetic analysis was used. Using I50 = Et/2 + Ki where Et = total enzyme concentration), we showed that TCDD inhibited cytochrome P-450d-dependent estradiol 2-hydroxylase activity with Ki equal to 8 nM. Association of TCDD with P-450d occurred within 2 min of inhibitor addition. Therefore, TCDD can be considered a tight binding inhibitor of cytochrome P-450d.

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“…Therefore, we have undertaken the synthesis of several oxygenated derivatives of TCDD (phenols and their methyl ethers) of high purity with a view to use them as GC or HPLC standards for characterizing TCDD metabolites and also for evaluating the toxicity of some of the phenolic compounds. In a previous study, Sawahata et al (1982) reported the synthesis of l-methoxy-2,3,7,8-tetrachloro-, 2-methoxy-1,3,7,8-tetrachloro-, and 3-methoxy-2,7,8trichlorodibenzo-p-dioxin and characterized their identity only by their mass spectra. Synthesis and spectral characterization of the latter two compounds and their hydroxy analogues in microgram quantities also have been reported by Mason and Safe (1986).…”

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Synthesis of oxygenated derivatives of 2,3,7,8-tetrachlorodibenzo-p-dioxin

Singh¹,

Kumar²

1993

J. Agric. Food Chem.

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Four monomethoxy, five dimethoxy and four dihydroxy derivatives of polychlorodibenzo-p-dioxin have been synthesized, and their physical and spectral properties (NMR and MS) have been reported. The general method for the synthesis of specific mono-and dimethoxy derivatives in reasonable yields has been found to be the condensation of 4,5-dichlorocatechol with appropriately substituted o-chloronitrobenzenes. The monomethoxy derivatives thus prepared were demethylated by boron tribromide dimethyl sulfide. Several mono-and dihydroxypolychlorodibenzo-p-dioxins have been identified as metabolites of the highly toxic environmental contaminant 2,3,7,8tetrachlorodibenzo-p-dioxin (TCDD). However, most of these metabolites have not been fully characterized due to the lack of appropriate standards. The availability of these synthetic oxygenated derivatives of TCDD can be used to establish the structure and the potential toxicity associated with these metabolites.

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Identification of metabolites of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) formed on incubation with isolated rat hepatocytes

Cited by 49 publications

References 8 publications

The role of structure in the disposition of halogenated aromatic xenobiotics.

The role of structure in the disposition of halogenated aromatic xenobiotics.

TCDD (2, 3, 7, 8‐tetrachlorodibenzo‐p‐dioxin) is a tight binding inhibitor of cytochrome p‐450D

Synthesis of oxygenated derivatives of 2,3,7,8-tetrachlorodibenzo-p-dioxin

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