The role of renal proximal tubule P450 enzymes in chloroform-induced nephrotoxicity: Utility of renal specific P450 reductase knockout mouse models

Liu, Senyan; Yao, Yunyi; Lu, Shijun; Aldous, Kenneth; Ding, Xinxin; Mei, Changlin; Gu, Jun

doi:10.1016/J.TAAP.2013.05.022

Title: The role of renal proximal tubule P450 enzymes in chloroform-induced nephrotoxicity: Utility of renal specific P450 reductase knockout mouse models

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Abstract

The kidney is a primary target for numerous toxic compounds. Cytochrome P450 enzymes (P450) are responsible for the metabolic activation of various chemical compounds, and in the kidney are predominantly expressed in proximal tubules. The aim of this study was to test the hypothesis that renal proximal tubular P450s are critical for nephrotoxicity caused by chemicals such as chloroform. We developed two new mouse models, one having proximal tubule-specific deletion of the cytochrome P450 reductase (Cpr) gene (the enzyme required for all microsomal P450 activities), designated proximal tubule-Cpr-null (PTCN), and the other having proximal tubule-specific rescue of CPR activity with the global suppression of CPR activity in all extra-proximal tubular tissues, designated extra-proximal tubule-Cpr-low (XPT-CL). The PTCN, XPT-CL, Cpr-low (CL), and wild-type (WT) mice were treated with a single oral dose of chloroform at 200 mg/kg. Blood, liver and kidney samples were obtained at 24 h after the treatment. Renal toxicity was assessed by measuring BUN and creatinine levels, and by pathological examination. The blood and tissue levels of chloroform were determined. The severity of toxicity was less in PTCN and CL mice, compared with that of WT and XPT-CL mice. There were no significant differences in chloroform levels inmore »« less

Authors:

Liu, Senyan ^[1]; Yao, Yunyi; Lu, Shijun; Aldous, Kenneth; Ding, Xinxin ^[2]; Mei, Changlin ^[1]; Gu, Jun ^[2]

Kidney Institute and Division of Nephrology, Changzheng Hospital, Shanghai 200003 (China)
Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York, Albany, NY 12201 (United States)

Publication Date:: Tue Oct 01 00:00:00 EDT 2013

OSTI Identifier:: 22285413

Resource Type:: Journal Article

Journal Name:: Toxicology and Applied Pharmacology

Additional Journal Information:: Journal Volume: 272; Journal Issue: 1; Other Information: Copyright (c) 2013 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X

Country of Publication:: United States

Language:: English

Subject:: 60 APPLIED LIFE SCIENCES; BLOOD; CHLOROFORM; CREATININE; ENZYMES; GENES; LIVER; METABOLIC ACTIVATION; MICE; TOXICITY

Citation Formats


                    Liu, Senyan, Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York, Albany, NY 12201, Yao, Yunyi, Lu, Shijun, Aldous, Kenneth, Ding, Xinxin, Mei, Changlin, and Gu, Jun. The role of renal proximal tubule P450 enzymes in chloroform-induced nephrotoxicity: Utility of renal specific P450 reductase knockout mouse models.  United States: N. p., 2013. 
        Web.  doi:10.1016/J.TAAP.2013.05.022.

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                    Liu, Senyan, Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York, Albany, NY 12201, Yao, Yunyi, Lu, Shijun, Aldous, Kenneth, Ding, Xinxin, Mei, Changlin, & Gu, Jun. The role of renal proximal tubule P450 enzymes in chloroform-induced nephrotoxicity: Utility of renal specific P450 reductase knockout mouse models.  United States.  https://doi.org/10.1016/J.TAAP.2013.05.022

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                    Liu, Senyan, Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York, Albany, NY 12201, Yao, Yunyi, Lu, Shijun, Aldous, Kenneth, Ding, Xinxin, Mei, Changlin, and Gu, Jun. 2013.  
        "The role of renal proximal tubule P450 enzymes in chloroform-induced nephrotoxicity: Utility of renal specific P450 reductase knockout mouse models".  United States.  https://doi.org/10.1016/J.TAAP.2013.05.022.

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@article{osti_22285413,

  title        = {The role of renal proximal tubule P450 enzymes in chloroform-induced nephrotoxicity: Utility of renal specific P450 reductase knockout mouse models},

  author       = {Liu, Senyan and Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York, Albany, NY 12201 and Yao, Yunyi and Lu, Shijun and Aldous, Kenneth and Ding, Xinxin and Mei, Changlin and Gu, Jun},

  abstractNote = {The kidney is a primary target for numerous toxic compounds. Cytochrome P450 enzymes (P450) are responsible for the metabolic activation of various chemical compounds, and in the kidney are predominantly expressed in proximal tubules. The aim of this study was to test the hypothesis that renal proximal tubular P450s are critical for nephrotoxicity caused by chemicals such as chloroform. We developed two new mouse models, one having proximal tubule-specific deletion of the cytochrome P450 reductase (Cpr) gene (the enzyme required for all microsomal P450 activities), designated proximal tubule-Cpr-null (PTCN), and the other having proximal tubule-specific rescue of CPR activity with the global suppression of CPR activity in all extra-proximal tubular tissues, designated extra-proximal tubule-Cpr-low (XPT-CL). The PTCN, XPT-CL, Cpr-low (CL), and wild-type (WT) mice were treated with a single oral dose of chloroform at 200 mg/kg. Blood, liver and kidney samples were obtained at 24 h after the treatment. Renal toxicity was assessed by measuring BUN and creatinine levels, and by pathological examination. The blood and tissue levels of chloroform were determined. The severity of toxicity was less in PTCN and CL mice, compared with that of WT and XPT-CL mice. There were no significant differences in chloroform levels in the blood, liver, or kidney, between PTCN and WT mice, or between XPT-CL and CL mice. These findings indicate that local P450-dependent activities play an important role in the nephrotoxicity induced by chloroform. Our results also demonstrate the usefulness of these novel mouse models for studies of chemical-induced kidney toxicity. - Highlights: • New mouse models were developed with varying P450 activities in the proximal tubule. • These mouse models were treated with chloroform, a nephrotoxicant. • Studies showed the importance of local P450s in chloroform-induced nephrotoxicity.},

  doi          = {10.1016/J.TAAP.2013.05.022},

  url          = {https://www.osti.gov/biblio/22285413},
  journal      = {Toxicology and Applied Pharmacology},

  issn         = {0041-008X},

  number       = 1,

  volume       = 272,

  place        = {United States},

  year         = {Tue Oct 01 00:00:00 EDT 2013},

  month        = {Tue Oct 01 00:00:00 EDT 2013}

}

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