The interactions of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 6-methyl-1,3,8-trichlorodibenzofuran (MCDF) in TCDD-induced porphyria

Abstract

Halogenated aryl hydrocarbon(HAH)-induced porphyria is caused by alteration of porphyrin metabolism and results in the accumulation of hepatic and urinary porphyrins. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (75 μg/kg) caused significant increases of hepatic porphyrin levels in C57BL/6 male, female and ovariectomized female, and C57BL/10 male mice 3 weeks after treatment. In contrast, 6-methyl-1,3,8,-trichlorodibenzofuran (MCDF) was inactive at a dose of 750 μmol/kg. Cotreatment with MCDF (750 μmol/kg) and 2,3,7,8- TCDD (75 μg/kg) resulted in partial antagonism of 2,3,7,8-TCDD-induced porphyrin accumulation in female but not in male mice. In female C57BL/6 mice, 2,3,7,8-TCDD-induced porphyria was accompanied by the induction of hepatic microsomal aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD) activities and the inhibition of uroporphyrinogen decarboxylase (UROD) activity. MCDF (750 μmol/kg) did not significantly affect these enzyme activities. In coadm inistration studies, MCDF partially antagonized 2,3,7,8-TCDDinduced hepatic porphyrin accumulation but did not affect the activities of hepatic AHH, EROD or UROD. These results demonstrate that the induction of the monooxygenase enzyme activities and the inhibition of UROD activity by 2,3,7,8-TCDD and the development of porphyria are not coordinately regulated in C57BL/6 female mice. In cultured chick embryo hepatocytes, 2,3,7,8-TCDD caused a significant increase in porphyrin levels and induced AHH and EROD activities. MCDF and Aroclor 1254 partially antagonized the 2,3,7,8-TCDDinduced AHH and EROD activities but not the porphyrin accumulation. The structure-induction relationships for several PCB congeners in these hepatocytes showed that the induction of AHH and EROD activities is structure-dependent; the most active congeners were substituted only in the para and meta positions and were approximately isostereomers of 2,3,7,8-TCDD. The stepwise introduction of ortho-chloro substituent gave PCB congeners with lower induction potencies. The difference between mice and cultured chick hepatocytes in their response to MCDF was probably due to the species-specific differences, or differences in the length of exposure to MCDF and 2,3,7,8-TCDD. However, the results of this research demonstrate that cultured chick embryo hepatocytes serve as a sensitive system for investigating HAH-induced toxic and biochemical responses (porphyria, and AHH and EROD induction) and their mechanism of action.