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Repression of intestinal drug metabolizing enzymes by the SV40 large T antigen

M T Sáenz-Robles1, D Toma, P Cantalupo

  • 1Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA.

Oncogene
|March 6, 2007
PubMed

Insights

The SV40 large T antigen (TAg) in intestinal cells lowers detoxification enzymes, impacting carcinogen and drug metabolism. This suggests a functional retinoblastoma pathway is vital for intestinal detoxification.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Toxicology

Background:

  • Detoxification enzymes and transporters in the liver and small intestine eliminate toxic compounds like carcinogens.
  • The SV40 large T antigen (TAg) is a viral protein known to interfere with cellular processes.

Purpose of the Study:

  • To investigate the effect of SV40 large T antigen (TAg) expression on detoxification systems in intestinal epithelial cells.
  • To determine the role of the retinoblastoma (Rb) pathway in TAg-mediated suppression of detoxification enzymes.

Main Methods:

  • Comparison of mRNA levels for drug metabolizing/detoxifying enzymes and transporters in TAg-expressing intestinal cells versus non-transgenic littermates.
  • Assessment of TAg's ability to block xenobiotic induction of these mRNAs.
  • Analysis of the role of the LXCXE motif in TAg and its interaction with the Rb family of tumor suppressors.

Main Results:

  • Intestinal epithelial cells expressing TAg showed significantly reduced mRNA levels for key detoxification enzymes and transporters.
  • TAg inhibited the induction of these detoxification-related mRNAs by xenobiotics.
  • The repression was dependent on an intact LXCXE motif in TAg, implicating Rb pathway inactivation.
  • TAg expression in the liver did not suppress P450 enzymes, indicating tissue-specific effects.

Conclusions:

  • A functional retinoblastoma pathway in the intestine is essential for the proper expression of the carcinogen detoxification system.
  • Loss of Rb tumor suppressor function may increase susceptibility to chemical injury in the intestine.
  • TAg-mediated suppression of detoxification enzymes has significant implications for understanding carcinogen and drug metabolism.

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