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Electrophile and antioxidant regulation of enzymes that detoxify carcinogens

T Prestera1, P Talalay

  • 1Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Proceedings of the National Academy of Sciences of the United States of America
|September 12, 1995
PubMed

Insights

Electrophile-responsive/antioxidant-responsive elements (EpRE/ARE) mediate the induction of detoxifying enzymes. Specific proteins bind to EpRE/ARE, activating these elements in response to various compounds.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Toxicology

Background:

  • Phase 2 detoxication enzymes, including glutathione S-transferases (GSTs) and NAD(P)H: (quinone-acceptor) oxidoreductase (QR), are crucial for cellular defense against toxic and carcinogenic compounds.
  • The induction of these enzymes is regulated by specific DNA sequences known as electrophile-responsive/antioxidant-responsive elements (EpRE/ARE).

Purpose of the Study:

  • To elucidate the mechanism by which EpRE/AREs are activated by electrophilic compounds and antioxidants.
  • To determine if EpRE/ARE activation is mediated by specific DNA-binding proteins distinct from those interacting with phorbol 12-tetradecanoate 13-acetate (TPA)-responsive elements (TREs).

Main Methods:

  • Transient gene expression assays using growth hormone reporter constructs containing either the wild-type EpRE/ARE from the mouse GST Ya gene or consensus TREs.
  • Comparison of reporter construct activation in Hep G2 (human) and Hepa 1c1c7 (murine) hepatoma cells, as well as in F9 cells lacking endogenous TRE-binding proteins.
  • Measurement of NAD(P)H: (quinone-acceptor) oxidoreductase (QR) activity.

Main Results:

  • The wild-type EpRE/ARE construct showed significant induction by a wide range of electrophilic compounds and antioxidants (e.g., tert-butylhydroquinone, sulforaphane, HgCl2).
  • Constructs containing consensus TREs did not exhibit significant induction by these compounds, unlike the EpRE/ARE construct.
  • TPA treatment in combination with other inducers resulted in additive or synergistic effects on the EpRE/ARE construct, while TRE construct induction was similar to TPA alone.
  • F9 cells, lacking TRE-binding proteins, showed substantial induction of the EpRE/ARE reporter construct and QR activity.

Conclusions:

  • Activation of EpRE/AREs by electrophilic and antioxidant inducers is mediated by specific EpRE/ARE-binding proteins.
  • This mechanism is distinct from the activation pathways involving TREs.

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