Dose-response relationship of cytochrome P4501b1 mRNA induction by 2,3,7,8-tetrachlorodibenzo- p -dioxin in livers of C57BL/6J and DBA/2J mice

Abstract

The dose-response relationship of cytochrome P4501b1 (Cyp1b1) and Cyp1a1 induction in livers of TCDD-treated female C57BL/6J and DBA/2J mice are described. The animals were treated i.p. with 0.001, 0.01, 0.1, 1, 10 and 50 micrograms TCDD/kg for 24 h, and Cyp1b1 and Cyp1a1 mRNA expression was analyzed by RT-PCR. In the livers of both mouse strains, the Cyp1b1 and Cyp1a1 mRNA content was increased after TCDD exposure in a dose-dependent manner. These effects were more pronounced in TCDD-responsive C57BL/6J mice than in the less responsive DBA/2J mice, although Cyp1a1 was more responsive to TCDD than Cyp1b1 in both strains. The calculated ED50 values for Cyp1b1 and Cyp1a1 induction in livers of TCDD-treated C57BL/6J mice were 1.3 and 0.08 micrograms TCDD/kg, respectively. The corresponding values for half-maximal induction response in livers of DBA/2J mice were 3.4 micrograms TCDD/kg for Cyp1b1 and 1.5 micrograms TCDD/kg for Cyp1a1. These results show that Cyp1b1 mRNA expression is less inducible by TCDD than Cyp1a1. Both genes are highly inducible in TCDD-responsive C57BL/6J mice expressing the high affinity arylhydrocarbon receptor (Ah receptor), suggesting that Cyp1b1, like Cyp1a1, is a potential Ah receptor-regulated gene.

Target cells for cytochrome P450-catalysed irreversible binding of 7,12-dimethylbenz[a]anthracene (DMBA) in rodent adrenal glands

“…The ability of the CYP1 inhibitors ellipticine, ANF and 1-EP to reduce [ 3 H]DMBA binding in cultured rat adrenal slices therefore indicates that the parenchymal binding in the zona fasciculata/reticularis was due to a local CYP1B1-catalysed formation of a reactive DMBA metabolite. The lack of DMBA binding in the zona fasciculata/reticularis in mouse slices is consistent with the observation that neither CYP1B1 mRNA nor protein has been found in mouse adrenals, even though TCDD induces CYP1B1 mRNA in mouse liver (Savas et al 1994;Abel et al 1996).…”

The Aryl Hydrocarbon Receptor-interacting Protein (AIP) Is Required for Dioxin-induced Hepatotoxicity but Not for the Induction of the Cyp1a1 and Cyp1a2 Genes

“…In line with this idea, the lower AHR concentrations in the Aip mutants may still be large enough to fully occupy "high affinity/availability" DREs within the genome, but the smaller pool of available receptors in Aip mutants is not large enough to fully occupy lower affinity enhancers. Data supporting the idea that different target genes may harbor differential responsiveness to the AHR include previous reports that the ED 50 for dioxin exposure using Cyp1b1 induction in liver as an end point is 3-24-fold higher than that for Cyp1a1 or Cyp1a2 induction (33)(34)(35)). …”

Comparison of the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced CYP1A1 gene expression profile in lymphocytes from mice, rats, and humans: Most potent induction in humans

“…The difference between their affinities correlates well with the strain-specific difference in AhR-dependent gene expression and sensitivity to TCDD toxicity between C57 mice and DBA mice. CYP1A1 and CYP1B1 are more strongly induced in C57 mice by TCDD exposure than in DBA mice (Abel et al, 1996). CYP1A1-mediated ethoxyresorufin O-deethylase (EROD) activity in the liver was induced at an ED50 of 1.1 and 16 g/kg in C57 mice and DBA mice, respectively, and hepatomegaly developed at doses of 3 g/kg or higher and 97.5 g/kg or higher, respectively (Weber et al, 1995).…”