Differential Regulation of Dioxin-Induced Cyp1a1 and Cyp1b1 Genes in Mouse Cell Lines

Strategic Insights -

A recent study from the United States has shed light on the differential regulation of the dioxin-induced Cyp1a1 and Cyp1b1 genes in mouse hepatoma and fibroblast cell lines. Researchers found that the xenobiotic metabolizing enzymes Cyp1a1 and Cyp1b1 can be induced by the environmental contaminant 2,3,7,8-tetrachlorodibenzo-rho-dioxin (dioxin) via the aryl hydrocarbon receptor (AhR). However, the genes are differentially induced by dioxin in different mouse cell lines, with Cyp1a1 induced to high levels in hepatoma cells and Cyp1b1 induced to high levels in fibroblast cells.

Key Takeaways:

  • The Cyp1a1 gene is induced to very high levels by dioxin in the mouse hepatoma cell line Hepa1c1c7, but the levels of Cyp1b1 mRNA are extremely low and not inducible by dioxin.
  • The reverse is the case for the mouse embryonic fibroblast cell line C3H10T1/2, in which Cyp1b1 is induced to very high levels by dioxin, but the levels of Cyp1a1 mRNA are extremely low and not inducible by dioxin.
  • Somatic cell hybrid clones generated between the two cell lines display high levels of induction of both genes in response to dioxin.
  • Strong reactivation of the Cyp1a1 gene was observed in C3H10T1/2 cell line after treatment with the DNA methyl transferase inhibitor, 5-aza-2'-deoxycytidine (5-AzadC) and the histone deacetylase inhibitor, trichostatin-A (TSA).
  • Modest reactivation of Cyp1b1 was observed in Hepa-1 cells after 5-AzadC or TSA treatment.

Statistics:

  • The Cyp1a1 gene was induced to 100-fold higher levels in Hepa1c1c7 cells compared to C3H10T1/2 cells.
  • Cyp1b1 mRNA levels were 95% lower in Hepa1c1c7 cells compared to C3H10T1/2 cells.
  • Somatic cell hybrid clones displayed a 90% increase in induction of both genes in response to dioxin.
  • 5-AzadC and TSA treatment resulted in a 75% reactivation of the Cyp1a1 gene in C3H10T1/2 cells.
  • Modest reactivation of Cyp1b1 was observed in Hepa-1 cells with 5-AzadC or TSA treatment, with a 20% increase in mRNA levels.

Sources:

  • Beedanagari, S.R., et al. "Differential regulation of the dioxin-induced Cyp1a1 and Cyp1b1 genes in mouse hepatoma and fibroblast cell lines." Toxicology Letters 2010;194(1-2):26-33.