2,3,7,8-Tetrachlorodibenzo-<i>p</i>-Dioxin: Covalent Binding of Reactive Metabolic Intermediates Principally to Protein <i>in vitro</i>

Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is metabolized by the mouse liver cytochrome P-450-mediated monooxygenase system to reactive intermediates which bind ‘cova-lently’ to cellular macromolecules. Although very difficult to quantitate, the presumably covalent binding to microsomal protein occurs between 120 and 2,640 times more readily than binding to deproteinized DNA in the in vitro reaction. Because of the extremely high rate of binding to protein rather than to DNA, it is visualized that TCDD metabolites may be so reactive that they bind in or near the P-450-active site where the TCDD is monooxygenated. This extreme reactivity may preclude the formation of detectable quantities of phenols, dihydrodiols, or conjugated products. The rate of TCDD metabolism is estimated to be between 9,000 and 36,000 times lower than the rate of P-450-mediated benzo[a]pyrene metabolism. To our knowledge, this is the first demonstration that TCDD is metabolized in any organism. There remains the possibility, however unlikely, that this covalently-bound radioactivity represents metabolites of contaminants -present in the radiolabeled TCDD sample in very minute amounts – rather than metabolites of tritiated TCDD itself. The possible relationship between P450-mediated metabolism of this environmental contaminant and its extreme toxicity or teratogenicity is discussed.

Tissue Distribution, Metabolism, and Excretion of 14C‐TCDD in a TCDD‐Susceptible and a TCDD‐Resistant Rat Straina

“…Moreover, the HPLC analysis showed that in both strains, the bulk of the label in the liver was linked to the parent compound, which is also in agreement with previous findings (Rose et al 1976). Although reactive metabolites of TCDD were found in one study on mice (Guenthner et al 1979), it is now generally believed that TCDD toxicity is due to the parent substance and not to its metabolites (Mason & Safe 1986;Weber et al 1982;Ramsey et al 1982;Beatty et al 1978). The levels of radioactivity in the liver were much the same in the two strains, even at 50 pg/kg of TCDD (autoradiographic data) which is a dose lethal to L-E but sublethal to H/W rats .…”

Antiestrogenicity of Clarified Slurry Oil and Two Crude Oils in a Human Breast-Cancer Cell Assay

“…Similar findings were reported in a study with benzo[k]fluoranthene (BkF) (Arcaro et al, 2000), in which it was found that the highest concentration, 5 µM, inhibited the metabolism of E 2 , while lower concentrations increased the metabolism. This inhibition was not found after treatment with tetrachlorodibenzod ioxin (TCDD; Arcaro et al, 2000), which is not as readily metabolized by the enzymes it induces (Guenthner et al, 1979;Philips & Grover, 1994). Furthermore, the effect on metabolism was dependent on the length of the exposure, as BkF itself was metabolized over time and was no longer available to compete with E 2 for the induced enzymes.…”

Degradation of 2,7-dichlorodibenzo-p-dioxin by the lignin-degrading basidiomycete Phanerochaete chrysosporium

“…Since TCDD and other highly chlorinated dioxins do not have an available 3-position for hydroxylation, they are relatively resistant to mammalian degradation (19,47). In contrast, P. chrysosponum initiates C-0-C bond cleavage via one-electron oxidations catalyzed by LiP.…”