THE IN VIVO AND IN VITRO METABOLISM OF 2,3,7,8-TETRACHLORODIBENZO-p-DIOXIN IN THE GOLDEN SYRIAN HAMSTER

Abstract

The hamster has been reported to be the least sensitive mammalian species to the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) with an LD50 value of > 3000 μg TCDD/kg. The excretion of radioactivity by hamsters was followed for up to 35 days following a single dose of radiolabeled TCDD. Similar half-life of elimination values of 12.0 ± 2.0 and 10.8 ± 2.4 days were obtained with the administration of [3H]- and [14C] TCDD, respectively. With both [3H]- and [14C] TCDD, approximately 35 and 50 percent of the radioactivity was eliminated in urine and feces, respectively. High performance liquid chromatography (hplc) of the urine and bile of animals receiving [14C] TCDD revealed one major and several minor radioactive peaks, none of which correspond to [14C] TCDD. The incubation of urine or bile with β-glucuronidase substantially altered the elution profile of the radioactive peaks suggesting that a glucuronide conjugate may be one of the major metabolites. Following the in vitro incubation of hamster hepatic microsomes with [3H]- or [14C) TCDD, a 6 to 9 fold increase in the unextractable radioactivity was observed. This was mediated by a heat sensitive system and required NADPH. Isolated hamster hepatocytes also demonstrated an ability to produce polar metabolites of [3H]-or [14C] TCDD. Analysis of the media from these incubations by hplc demonstrated several polar metabolite peaks similar to those observed in urine and bile.