Synthesis, biologic and toxic properties of 2,3,7,8-TCDD metabolites
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2-Hydroxy-3,7,8-trichlorodibenzo-p-dioxin has been identified as a major urinary metabolite of 2,3,7,8-TCDD in several laboratory animal studies. This compound was synthesized via coupling of 2,5-dichloro-4-nitroanisole with 4,5-dichlorocatechol in HMPA. The resultant 3-methoxy-3,7,8-trichlorodibenzo-p-dioxin product was demethylated in boron tribromide/methylene chloride to give 2-hydroxy-3,7,8-trichlorodibenzo-p-dioxin. The metabolite was administered at dose levels of 100, 1000 and 5000 ug/kg to immature male Wistar rats and the effects of this compound on body weight loss, thymic atrophy and hepatic microsomal monooxygenase enzyme induction were determined. Comparable dose-response studies for 2,3,7,8-TCDD were also carried out. At dose levels of 4-8 ug/kg 2,3,7,8-TCDD caused significant body weight loss and thymic atrophy in the Wistar rats whereas 2-hydroxy-3,7,8-trichlorodibenzo-p-dioxin did not elicit these toxic effects at a dose level of 5000 ug/kg. The ED50 values for the induction of hepatic microsomal benzo[a]pyrene hydroxylase and ethoxyresorufin O-deethylase were 1.25 and 2.35 ug/kg for 2,3,7,8-TCDD and 2,820 and 3550 ug/kg for 2-hydroxy-3,7,8-trichlorodibenzo-p-dioxin respectively. These results demonstrated that 2-hydroxy-3,7,8-trichlorodibenzo-p-dioxin is at least 3 orders of magnitude less toxic than 2,3,7,8-TCDD and this is consistent with the lower receptor binding affinity of the metabolite coupled with the expected more rapid clearance of this compound. © 1986.
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