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

Oncogene volume 26, pages 5124–5131 (2007)Cite this article

Abstract

Toxic compounds such as carcinogens are removed from the body by the action of a series of detoxifying enzymes and transporters expressed in the liver and the small intestine. We have found that intestinal epithelial cells expressing the SV40 large T antigen (TAg) contain significantly lower levels of mRNAs, encoding several drug metabolizing/detoxifying enzymes and transporters compared to their non-transgenic littermates. In addition, TAg blocks the induction of these mRNAs by xenobiotics. The repression depends on an intact LXCXE motif in TAg, suggesting that inactivation of the retinoblastoma (Rb) family of tumor suppressors plays a role in the process. These results imply that a functional Rb pathway in the intestine is necessary for the expression of the detoxification system used to clear carcinogens, and suggest that loss of this tumor suppressor might alter susceptibility to chemical injury. In addition, the effect of TAg on the detoxification pathway appears to be tissue-specific, as its ectopic expression in the liver failed to suppress the P450 enzymes. The TAg-mediated suppression of drug metabolizing/detoxifying enzymes may have broad implications in the metabolism and mechanism of action of both carcinogens and prescription drugs.

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Acknowledgements

We thank Ying Mu for his help in transfection studies. This work was supported by NIH Grants CA40586 and CA098956 to JMP and ES012479 and CA107011 to WX. HG is supported by a Susan G Komen Breast Cancer Foundation Postdoctoral Fellowship (PDF053458).

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Author notes

  1. M T Sáenz-Robles and D Toma: These two authors contributed equally to this work.

Authors and Affiliations

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

    M T Sáenz-Robles, P Cantalupo, C Edwards & J M Pipas

  2. Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA

    D Toma, J Zhou, H Gong & W Xie

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  1. M T Sáenz-Robles
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  2. D Toma
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  3. P Cantalupo
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  4. J Zhou
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  5. H Gong
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  6. C Edwards
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  7. J M Pipas
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  8. W Xie
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Correspondence to J M Pipas or W Xie.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Sáenz-Robles, M., Toma, D., Cantalupo, P. et al. Repression of intestinal drug metabolizing enzymes by the SV40 large T antigen. Oncogene 26, 5124–5131 (2007). https://doi.org/10.1038/sj.onc.1210310

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