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Cytochrome P450 1B1: a target for inhibition in anticarcinogenesis strategies

F Peter Guengerich1, Young-Jin Chun, Donghak Kim

  • 1Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, 638 Robinson Research Building, 23rd Pierce Avenue, Nashville, TN 37232-0146, USA. guengerich@toxicology.mc.vanderbilt.edu

Mutation Research
|March 12, 2003
PubMed

Insights

Researchers identified a selective inhibitor, 2,4,3

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Cytochrome P450 (P450) 1B1 is implicated in activating environmental mutagens and estrogen metabolism, key factors in hormonal carcinogenesis.
  • P450 1B1 is expressed in human tissues where cancers frequently occur, including prostate, ovary, uterus, and mammary gland.

Purpose of the Study:

  • To investigate the activities of human P450 1B1 allelic variants in mutagen activation and estrogen metabolism.
  • To develop selective chemical inhibitors of P450 1B1 for potential cancer prevention strategies.

Main Methods:

  • Assayed activities of human P450 1B1 allelic variants.
  • Screened chemical inhibitors including 2-ethynylpyrene, alpha-naphthoflavone, resveratrol, and synthetic stilbenes.
  • Determined inhibition kinetics and selectivity of identified compounds against P450 1B1 and P450 1A1.

Main Results:

  • Discovered 2,4,3',5'-tetramethoxystilbene as a potent and selective competitive inhibitor of P450 1B1 (K(i) = 3nM), resistant to metabolism.
  • Demonstrated that 2,4,3',5'-tetramethoxystilbene blocks estrogen 4-hydroxylation and heterocyclic amine activation to mutagens.
  • Observed suppression of P450 1B1 expression and human mammary tumor cell growth by 2,4,3',5'-tetramethoxystilbene.
  • Identified 3,3',4',5,5'-pentamethoxystilbene as a selective P450 1A1 inhibitor that suppresses P450 1A1 expression.

Conclusions:

  • Substituted stilbenes, particularly 2,4,3',5'-tetramethoxystilbene, show promise as selective inhibitors of P450 1B1.
  • These compounds may offer a novel approach to preventing cancers linked to estrogen metabolism and xenobiotic activation.

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