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Potent inhibition of human cytochrome P450 1B1 by tetramethoxystilbene

Young-Jin Chun1, Young-Kun Oh, Beom Joon Kim

  • 1College of Pharmacy, Chung-Ang University, Seoul 156-756, Republic of Korea. yjchun@cau.ac.kr

Toxicology Letters
|May 26, 2009
PubMed

Insights

2,2

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Human cytochrome P450 1B1 (CYP1B1) is predominantly found in extrahepatic tissues.
  • CYP1B1 overexpression is observed in various human tumors.
  • Metabolic activation of 17beta-estradiol (E2) by CYP1B1 is implicated in mammary carcinogenesis.

Purpose of the Study:

  • To investigate the inhibitory potential of 2,2',4,6'-tetramethoxystilbene (TMS) on human CYP1B1.
  • To assess the selectivity of TMS against other cytochrome P450 enzymes.
  • To evaluate the effect of TMS on CYP1B1 gene expression.

Main Methods:

  • Enzyme inhibition assays using recombinant human CYP1B1 (expressed in E. coli membranes or purified enzyme).
  • Assays included ethoxyresorufin O-deethylation (EROD) activity measurement.
  • Gene expression analysis in human tumor cells (HepG2, MCF-10A) treated with TCDD.

Main Results:

  • 2,2',4,6'-TMS demonstrated potent and selective inhibition of CYP1B1 EROD activity (IC50 = 2 nM).
  • TMS showed significant selectivity for CYP1B1 over CYP1A1 (175-fold) and CYP1A2 (85-fold).
  • TMS acted as a noncompetitive inhibitor for CYP1A1 and CYP1B1 and suppressed TCDD-induced CYP1B1 gene expression.

Conclusions:

  • 2,2',4,6'-TMS is a highly potent and selective inhibitor of human CYP1B1.
  • TMS also functions as a suppressor of CYP1B1 expression.
  • 2,2',4,6'-TMS may serve as a valuable research tool for studying human CYP1B1 properties.

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