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Effect of several analogs of 2,4,6-triphenyldioxane-1,3 on CYP2B induction in mouse liver

Vladimir Pustylnyak1, Yuliya Kazakova, Andrei Yarushkin

  • 1Institute of Molecular Biology and Biophysics, SB RAMS, Novosibirsk, Russia. pustylnyak@ngs.ru

Chemico-Biological Interactions
|October 11, 2011
PubMed

Insights

Minor structural changes in 2,4,6-Triphenyldioxane-1,3 (TPD) analogs significantly altered their ability to induce CYP2B in mouse livers. Four analogs demonstrated dose-dependent induction, suggesting activation of the constitutive androstane receptor (CAR).

Area of Science:

  • Pharmacology
  • Biochemistry
  • Drug Metabolism

Background:

  • 2,4,6-Triphenyldioxane-1,3 (TPD) effectively induces CYP2B in rats but not in mice.
  • Investigating TPD analogs is crucial for understanding structure-activity relationships in drug metabolism.
  • CYP2B enzymes play a significant role in xenobiotic metabolism and detoxification.

Purpose of the Study:

  • To evaluate the efficacy of synthesized TPD analogs in inducing CYP2B in mouse livers.
  • To characterize the dose-response relationship and potency of active TPD analogs.
  • To elucidate the molecular mechanisms underlying CYP2B induction by TPD analogs.

Main Methods:

  • Synthesis and administration of six TPD analogs with varying substituents.
  • Determination of ED50 values using sigmoidal dose-response curves.
  • Analysis of CYP2B protein levels (Western blot) and mRNA expression (RT-PCR).
  • Chromatin immunoprecipitation (ChIP) assay to assess constitutive androstane receptor (CAR) recruitment.

Main Results:

  • Four TPD analogs (transpDMA, transpNO2, transpF, transpMeO) induced mouse CYP2B in a dose-dependent manner.
  • All active analogs exhibited similar potencies in inducing CYP2B.
  • Increased CYP2B activity correlated with elevated CYP2B protein and cyp2b10 mRNA levels.
  • Compound-induced CYP2B expression involved enhanced recruitment of CAR to the PBREM site on the cyp2b10 gene.

Conclusions:

  • Substituent modifications on the TPD scaffold dramatically influence its CYP2B-inducing activity in mice.
  • TPD analogs likely activate mouse CAR, leading to the transcriptional upregulation of cyp2b10.
  • These findings provide insights into the development of selective CYP2B modulators.

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