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Induced expression of drug metabolizing enzymes by preventive agents: role of the antioxidant response element

Ronald A Lubet1, Ruisheng Yao, Clinton J Grubbs

  • 1Division of Cancer Prevention, National Cancer Institute, Executive Plaza North, Suite 2110, 6130 Executive Boulevard, Bethesda, MD 20852, USA. lubetr@mail.nih.gov

Chemico-Biological Interactions
|August 22, 2009
PubMed

Insights

Identifying cancer prevention agents is crucial. This study examined how various compounds affect drug-metabolizing genes in rats, finding limited correlation between gene induction and anti-tumor activity, questioning simple gene markers for prevention efficacy.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Toxicology

Background:

  • Cancer prevention strategies aim to identify agents that inhibit tumor initiation.
  • Drug-metabolizing enzymes play a role in detoxification and cancer prevention.
  • Understanding how different agents induce these enzymes is key to evaluating their potential.

Purpose of the Study:

  • To investigate the ability of chemically diverse agents to induce drug metabolizing genes in rat livers.
  • To examine the correlation between agent-induced gene expression and their known preventive activity in tumor models.
  • To question the validity of using single gene induction as a surrogate marker for overall anti-tumor efficacy.

Main Methods:

  • Sprague-Dawley rats were treated for 7 days with various Phase I/II or pure Phase II inducers.
  • Agents included 5,6-benzoflavone, diallyl sulfide, ethoxyquin, phenobarbital, 1,2-dithiol-3-thione, and cyclopentadithiolthione.
  • Liver RNA expression was analyzed using oligonucleotide microarrays.

Main Results:

  • Different agents produced unique gene expression profiles.
  • Specific induction ratios were observed for quinone oxidoreductase, glutathione transferase Pi, and aldehyde keto reductase 7A3.
  • A broader analysis of Phase II enzymes revealed no clear induction pattern.
  • Limited correlation was found between agent-induced gene expression and published tumor prevention data.

Conclusions:

  • The induction profiles of drug-metabolizing genes vary significantly among different chemical agents.
  • Measuring the induction of a single gene, like quinone reductase, may not accurately reflect overall Phase II enzyme induction or anti-tumor potential.
  • Further research is needed to establish reliable biomarkers for cancer prevention agents.

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