Metabolic stability of 2, 3, 7, 8-tetrachlorodibenzo-P-dioxin in mammalian liver microsomal systems and in living mice

Dibenzo-p-dioxin is rapidly converted by microsome-NADPH systems, prepared from mouse, rat, and rabbit liver, and by intraperitoneally treated mice into unidentified, polar metabolite(s) that, in living mice, appear in the urine. In contrast, not any of these three liver microsome-NADPH systems convert 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin into either trichlorodibenzo-p-dioxin or water-soluble products. In living mice, the tetrachloro compound, injected at the LD₅₀ dose, is either not at all or not extensively converted to water-soluble products; the feces are the major route of elimination, possibly via the bile. A large proportion of the administered tetrachlorodibenzo-p-dioxin persists in unmetabolized form in the liver, partially concentrated in the microsomal fraction, 11 to 20 days after treatment. The metabolic stability and localization of the tetrachloro material indicate that the unmetabolized compound, rather than a metabolite, probably is responsible for its toxic effects in mammals and that the endoplasmic reticulum of the liver is a possible site of action.