| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Center for Pharmacogenetics (H.G., Y.M., J.H.L., S.P.S.S., D.T., S.R., W.X.), Departments of Pharmaceutical Sciences (H.G., Y.M., J.H.L., S.P.S.S., D.T., S.R., B.W.D., W.X.) and Pharmacology (S.V.S., W.X.), and University of Pittsburgh Cancer Institute, Departments of Environmental and Occupational Health (V.E.K.) and Chemistry (B.W.D.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261; and Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences (S.P.S., P.Z.), Little Rock, Arkansas 72205
Address all correspondence and requests for reprints to: Dr. Wen Xie, Center for Pharmacogenetics, 633 Salk Hall, University of Pittsburgh, Pittsburgh, Pennsylvania 15261. E-mail: wex6{at}pitt.edu.
Efficient handling of oxidative stress is critical for the survival of organisms. The orphan nuclear receptor pregnane X receptor (PXR) is important in xenobiotic detoxification through its regulation of phase I and phase II drug-metabolizing/detoxifying enzymes and transporters. In this study we unexpectedly found that the expression of an activated human PXR in transgenic female mice resulted in a heightened sensitivity to paraquat, an oxidative xenobiotic toxicant. Heightened paraquat sensitivity was also seen in wild-type mice treated with the mouse PXR agonist pregnenolone-16
-carbonitrile. The PXR-induced paraquat sensitivity was associated with decreased activities of superoxide dismutase and catalase, enzymes that scavenge superoxide and hydrogen peroxide, respectively. Paradoxically, the general expression and activity of glutathione S-transferases, a family of phase II enzymes that detoxify electrophilic and cytotoxic substrates, was also induced in the transgenic mice. PXR regulates glutathione S-transferase expression in an isozyme-, tissue-, and sex-specific manner, and this regulation is independent of the nuclear factor-erythroid 2 p45-related factor 2/Kelch-like Ech-associated protein 1 pathway. In cell cultures, expression of activated human PXR sensitizes the cancerous colon and liver cells to the cytotoxic effect of paraquat, which is associated with an increased production of the reactive oxygen species. The current study reveals a novel function of PXR in the mammalian oxidative stress response, and this regulatory pathway may be implicated in carcinogenesis by sensitizing normal and cancerous tissues to oxidative cellular damage.
NURSA Molecule Pages Link:
This article has been cited by other articles:
 |
|
 |
|
  J.-Y. Cho, D. W. Kang, X. Ma, S.-H. Ahn, K. W. Krausz, H. Luecke, J. R. Idle, and F. J. Gonzalez Metabolomics reveals a novel vitamin E metabolite and attenuated vitamin E metabolism upon PXR activation J. Lipid Res., May 1, 2009; 50(5): 924 - 937. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Gong, M. J. Jarzynka, T. J. Cole, J. H. Lee, T. Wada, B. Zhang, J. Gao, W.-C. Song, D. B. DeFranco, S.-Y. Cheng, et al. Glucocorticoids Antagonize Estrogens by Glucocorticoid Receptor-Mediated Activation of Estrogen Sulfotransferase Cancer Res., September 15, 2008; 68(18): 7386 - 7393. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Gupta, M. Venkatesh, H. Wang, S. Kim, M. Sinz, G. L. Goldberg, K. Whitney, C. Longley, and S. Mani Expanding the Roles for Pregnane X Receptor in Cancer: Proliferation and Drug Resistance in Ovarian Cancer Clin. Cancer Res., September 1, 2008; 14(17): 5332 - 5340. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Lichti-Kaiser and J. L. Staudinger The Traditional Chinese Herbal Remedy Tian Xian Activates Pregnane X Receptor and Induces CYP3A Gene Expression in Hepatocytes Drug Metab. Dispos., August 1, 2008; 36(8): 1538 - 1545. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Zhou, M. Liu, Y. Zhai, and W. Xie The Antiapoptotic Role of Pregnane X Receptor in Human Colon Cancer Cells Mol. Endocrinol., April 1, 2008; 22(4): 868 - 880. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Gong, P. Guo, Y. Zhai, J. Zhou, H. Uppal, M. J. Jarzynka, W.-C. Song, S.-Y. Cheng, and W. Xie Estrogen Deprivation and Inhibition of Breast Cancer Growth in Vivo through Activation of the Orphan Nuclear Receptor Liver X Receptor Mol. Endocrinol., August 1, 2007; 21(8): 1781 - 1790. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. K. Pacyniak, X. Cheng, M. L. Cunningham, K. Crofton, C. D. Klaassen, and G. L. Guo The Flame Retardants, Polybrominated Diphenyl Ethers, Are Pregnane X Receptor Activators Toxicol. Sci., May 1, 2007; 97(1): 94 - 102. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. L. Urquhart, R. G. Tirona, and R. B. Kim Nuclear Receptors and the Regulation of Drug-Metabolizing Enzymes and Drug Transporters: Implications for Interindividual Variability in Response to Drugs J. Clin. Pharmacol., May 1, 2007; 47(5): 566 - 578. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Ma, Y. Shah, C. Cheung, G. L. Guo, L. Feigenbaum, K. W. Krausz, J. R. Idle, and F. J. Gonzalez The Pregnane X Receptor Gene-Humanized Mouse: A Model for Investigating Drug-Drug Interactions Mediated by Cytochromes P450 3A Drug Metab. Dispos., February 1, 2007; 35(2): 194 - 200. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Zhai, H. V. Pai, J. Zhou, J. A. Amico, R. R. Vollmer, and W. Xie Activation of Pregnane X Receptor Disrupts Glucocorticoid and Mineralocorticoid Homeostasis Mol. Endocrinol., January 1, 2007; 21(1): 138 - 147. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Zhou, Y. Zhai, Y. Mu, H. Gong, H. Uppal, D. Toma, S. Ren, R. M. Evans, and W. Xie A Novel Pregnane X Receptor-mediated and Sterol Regulatory Element-binding Protein-independent Lipogenic Pathway J. Biol. Chem., May 26, 2006; 281(21): 15013 - 15020. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
