2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced porphyria in genetically inbred mice: Partial antagonism and mechanistic studies

C. Yao, S. Safe

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) (233 nmol/kg) causes a significant increase of hepatic uroporphyrin, heptacarboxyporphyrin, and total porphyrins in female C57BL/6 mice, ovariectomized C57BL/6 mice, male C57BL/10 mice, and male C57BL/6 mice 3 weeks after treatment. In contrast, 6-methyl-1,3,8-trichlorodibenzofuran (MCDF) was inactive at a dose of 750 μmol/kg. Cotreatment of the mice with TCDD (233 mol/kg) plus MCDF (750 μmol/kg) resulted in partial antagonism of TCDD-induced hepatic porphyrin accumulation only in the female mice. Parallel studies in female C57BL/6 mice showed that the TCDD-induced porphyria was accompanied by the induction of hepatic microsomal aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD) activities and the depression of uroporphyrinogen decarboxylase (UROD). MCDF (750 μmol/kg) did not significantly affect these enzymes. In the cotreatment studies (MCDF plus TCDD), MCDF partially antagonized TCDD-induced hepatic porphyrin accumulation but did not affect the levels of hepatic AHH, EROD, or UROD. These results indicate that other factors, in addition to the induction of cytochrome P450-dependent monooxygenases and depressed UROD activity, are important in TCDD-induced porphyria in C57BL/6 female mice.

Original languageEnglish (US)
Pages (from-to)208-216
Number of pages9
JournalToxicology and Applied Pharmacology
Volume100
Issue number2
DOIs
StatePublished - Sep 1 1989

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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