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Research ArticleSymposium Report

NADPH–Cytochrome P450 Oxidoreductase: Roles in Physiology, Pharmacology, and Toxicology

David S. Riddick, Xinxin Ding, C. Roland Wolf, Todd D. Porter, Amit V. Pandey, Qing-Yu Zhang, Jun Gu, Robert D. Finn, Sebastien Ronseaux, Lesley A. McLaughlin, Colin J. Henderson, Ling Zou and Christa E. Flück
Drug Metabolism and Disposition January 2013, 41 (1) 12-23; DOI: https://doi.org/10.1124/dmd.112.048991
David S. Riddick
Department of Pharmacology and Toxicology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada (D.S.R.); Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany, Albany, New York (X.D., Q.-Y.Z., J.G.); Molecular Pharmacology Group, Division of Cancer Research, University of Dundee, and Jacqui Wood Cancer Centre, Ninewells Hospital and Medical School, Dundee, United Kingdom (C.R.W., R.D.F., S.R., L.A.M., C.J.H.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.D.P., L.Z.); Department of Pediatrics, Division of Pediatric Endocrinology and Diabetology, and Department of Clinical Research, University of Bern, Bern, Switzerland (A.V.P., C.E.F.)
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Xinxin Ding
Department of Pharmacology and Toxicology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada (D.S.R.); Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany, Albany, New York (X.D., Q.-Y.Z., J.G.); Molecular Pharmacology Group, Division of Cancer Research, University of Dundee, and Jacqui Wood Cancer Centre, Ninewells Hospital and Medical School, Dundee, United Kingdom (C.R.W., R.D.F., S.R., L.A.M., C.J.H.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.D.P., L.Z.); Department of Pediatrics, Division of Pediatric Endocrinology and Diabetology, and Department of Clinical Research, University of Bern, Bern, Switzerland (A.V.P., C.E.F.)
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C. Roland Wolf
Department of Pharmacology and Toxicology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada (D.S.R.); Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany, Albany, New York (X.D., Q.-Y.Z., J.G.); Molecular Pharmacology Group, Division of Cancer Research, University of Dundee, and Jacqui Wood Cancer Centre, Ninewells Hospital and Medical School, Dundee, United Kingdom (C.R.W., R.D.F., S.R., L.A.M., C.J.H.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.D.P., L.Z.); Department of Pediatrics, Division of Pediatric Endocrinology and Diabetology, and Department of Clinical Research, University of Bern, Bern, Switzerland (A.V.P., C.E.F.)
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Todd D. Porter
Department of Pharmacology and Toxicology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada (D.S.R.); Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany, Albany, New York (X.D., Q.-Y.Z., J.G.); Molecular Pharmacology Group, Division of Cancer Research, University of Dundee, and Jacqui Wood Cancer Centre, Ninewells Hospital and Medical School, Dundee, United Kingdom (C.R.W., R.D.F., S.R., L.A.M., C.J.H.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.D.P., L.Z.); Department of Pediatrics, Division of Pediatric Endocrinology and Diabetology, and Department of Clinical Research, University of Bern, Bern, Switzerland (A.V.P., C.E.F.)
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Amit V. Pandey
Department of Pharmacology and Toxicology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada (D.S.R.); Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany, Albany, New York (X.D., Q.-Y.Z., J.G.); Molecular Pharmacology Group, Division of Cancer Research, University of Dundee, and Jacqui Wood Cancer Centre, Ninewells Hospital and Medical School, Dundee, United Kingdom (C.R.W., R.D.F., S.R., L.A.M., C.J.H.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.D.P., L.Z.); Department of Pediatrics, Division of Pediatric Endocrinology and Diabetology, and Department of Clinical Research, University of Bern, Bern, Switzerland (A.V.P., C.E.F.)
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Qing-Yu Zhang
Department of Pharmacology and Toxicology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada (D.S.R.); Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany, Albany, New York (X.D., Q.-Y.Z., J.G.); Molecular Pharmacology Group, Division of Cancer Research, University of Dundee, and Jacqui Wood Cancer Centre, Ninewells Hospital and Medical School, Dundee, United Kingdom (C.R.W., R.D.F., S.R., L.A.M., C.J.H.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.D.P., L.Z.); Department of Pediatrics, Division of Pediatric Endocrinology and Diabetology, and Department of Clinical Research, University of Bern, Bern, Switzerland (A.V.P., C.E.F.)
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Jun Gu
Department of Pharmacology and Toxicology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada (D.S.R.); Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany, Albany, New York (X.D., Q.-Y.Z., J.G.); Molecular Pharmacology Group, Division of Cancer Research, University of Dundee, and Jacqui Wood Cancer Centre, Ninewells Hospital and Medical School, Dundee, United Kingdom (C.R.W., R.D.F., S.R., L.A.M., C.J.H.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.D.P., L.Z.); Department of Pediatrics, Division of Pediatric Endocrinology and Diabetology, and Department of Clinical Research, University of Bern, Bern, Switzerland (A.V.P., C.E.F.)
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Robert D. Finn
Department of Pharmacology and Toxicology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada (D.S.R.); Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany, Albany, New York (X.D., Q.-Y.Z., J.G.); Molecular Pharmacology Group, Division of Cancer Research, University of Dundee, and Jacqui Wood Cancer Centre, Ninewells Hospital and Medical School, Dundee, United Kingdom (C.R.W., R.D.F., S.R., L.A.M., C.J.H.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.D.P., L.Z.); Department of Pediatrics, Division of Pediatric Endocrinology and Diabetology, and Department of Clinical Research, University of Bern, Bern, Switzerland (A.V.P., C.E.F.)
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Sebastien Ronseaux
Department of Pharmacology and Toxicology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada (D.S.R.); Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany, Albany, New York (X.D., Q.-Y.Z., J.G.); Molecular Pharmacology Group, Division of Cancer Research, University of Dundee, and Jacqui Wood Cancer Centre, Ninewells Hospital and Medical School, Dundee, United Kingdom (C.R.W., R.D.F., S.R., L.A.M., C.J.H.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.D.P., L.Z.); Department of Pediatrics, Division of Pediatric Endocrinology and Diabetology, and Department of Clinical Research, University of Bern, Bern, Switzerland (A.V.P., C.E.F.)
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Lesley A. McLaughlin
Department of Pharmacology and Toxicology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada (D.S.R.); Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany, Albany, New York (X.D., Q.-Y.Z., J.G.); Molecular Pharmacology Group, Division of Cancer Research, University of Dundee, and Jacqui Wood Cancer Centre, Ninewells Hospital and Medical School, Dundee, United Kingdom (C.R.W., R.D.F., S.R., L.A.M., C.J.H.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.D.P., L.Z.); Department of Pediatrics, Division of Pediatric Endocrinology and Diabetology, and Department of Clinical Research, University of Bern, Bern, Switzerland (A.V.P., C.E.F.)
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Colin J. Henderson
Department of Pharmacology and Toxicology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada (D.S.R.); Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany, Albany, New York (X.D., Q.-Y.Z., J.G.); Molecular Pharmacology Group, Division of Cancer Research, University of Dundee, and Jacqui Wood Cancer Centre, Ninewells Hospital and Medical School, Dundee, United Kingdom (C.R.W., R.D.F., S.R., L.A.M., C.J.H.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.D.P., L.Z.); Department of Pediatrics, Division of Pediatric Endocrinology and Diabetology, and Department of Clinical Research, University of Bern, Bern, Switzerland (A.V.P., C.E.F.)
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Ling Zou
Department of Pharmacology and Toxicology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada (D.S.R.); Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany, Albany, New York (X.D., Q.-Y.Z., J.G.); Molecular Pharmacology Group, Division of Cancer Research, University of Dundee, and Jacqui Wood Cancer Centre, Ninewells Hospital and Medical School, Dundee, United Kingdom (C.R.W., R.D.F., S.R., L.A.M., C.J.H.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.D.P., L.Z.); Department of Pediatrics, Division of Pediatric Endocrinology and Diabetology, and Department of Clinical Research, University of Bern, Bern, Switzerland (A.V.P., C.E.F.)
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Christa E. Flück
Department of Pharmacology and Toxicology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada (D.S.R.); Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany, Albany, New York (X.D., Q.-Y.Z., J.G.); Molecular Pharmacology Group, Division of Cancer Research, University of Dundee, and Jacqui Wood Cancer Centre, Ninewells Hospital and Medical School, Dundee, United Kingdom (C.R.W., R.D.F., S.R., L.A.M., C.J.H.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.D.P., L.Z.); Department of Pediatrics, Division of Pediatric Endocrinology and Diabetology, and Department of Clinical Research, University of Bern, Bern, Switzerland (A.V.P., C.E.F.)
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Abstract

This is a report on a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics and held at the Experimental Biology 2012 meeting in San Diego, California, on April 25, 2012. The symposium speakers summarized and critically evaluated our current understanding of the physiologic, pharmacological, and toxicological roles of NADPH–cytochrome P450 oxidoreductase (POR), a flavoprotein involved in electron transfer to microsomal cytochromes P450 (P450), cytochrome b5, squalene mono-oxygenase, and heme oxygenase. Considerable insight has been derived from the development and characterization of mouse models with conditional Por deletion in particular tissues or partial suppression of POR expression in all tissues. Additional mouse models with global or conditional hepatic deletion of cytochrome b5 are helping to clarify the P450 isoform- and substrate-specific influences of cytochrome b5 on P450 electron transfer and catalytic function. This symposium also considered studies using siRNA to suppress POR expression in a hepatoma cell–culture model to explore the basis of the hepatic lipidosis phenotype observed in mice with conditional deletion of Por in liver. The symposium concluded with a strong translational perspective, relating the basic science of human POR structure and function to the impacts of POR genetic variation on human drug and steroid metabolism.

Footnotes

  • This work was supported by the Canadian Institutes of Health Research [Grant MOP-93759]; the National Institutes of Health National Cancer Institute [Grant CA092596]; the National Institutes of Health National Institute of Environmental Health Sciences [Grants ES007462, ES018884]; the National Institutes of Health National Institute of General Medical Sciences [Grant GM082978]; the National Institutes of Health National Center for Complementary and Alternative Medicine [Grant AT005235]; Cancer Research UK [Programme Grant C4639/A5661]; and the Swiss National Science Foundation [Grants 3100A0-113719, 31003A-134926].

  • D.S.R., X.D., C.R.W., T.D.P., and A.V.P. contributed equally to this work.

  • dx.doi.org/10.1124/dmd.112.048991.

  • Received September 10, 2012.
  • Accepted October 19, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (1)
Drug Metabolism and Disposition
Vol. 41, Issue 1
1 Jan 2013
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Research ArticleSymposium Report

Biological Roles of NADPH–Cytochrome P450 Oxidoreductase

David S. Riddick, Xinxin Ding, C. Roland Wolf, Todd D. Porter, Amit V. Pandey, Qing-Yu Zhang, Jun Gu, Robert D. Finn, Sebastien Ronseaux, Lesley A. McLaughlin, Colin J. Henderson, Ling Zou and Christa E. Flück
Drug Metabolism and Disposition January 1, 2013, 41 (1) 12-23; DOI: https://doi.org/10.1124/dmd.112.048991

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Research ArticleSymposium Report

Biological Roles of NADPH–Cytochrome P450 Oxidoreductase

David S. Riddick, Xinxin Ding, C. Roland Wolf, Todd D. Porter, Amit V. Pandey, Qing-Yu Zhang, Jun Gu, Robert D. Finn, Sebastien Ronseaux, Lesley A. McLaughlin, Colin J. Henderson, Ling Zou and Christa E. Flück
Drug Metabolism and Disposition January 1, 2013, 41 (1) 12-23; DOI: https://doi.org/10.1124/dmd.112.048991
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  • Article
    • Abstract
    • Introduction
    • Engineered Mouse Models Harboring Null or Hypomorphic Alleles for NADPH–Cytochrome P450 Oxidoreductase
    • NADPH–Cytochrome P450 Oxidoreductase and Cytochrome b5 in Physiology, Drug Metabolism, and Cancer
    • Replication of the Hepatic Lipidosis Seen in Hepatic Por-Null Mice in a Hepatoma Cell–Culture Model: A Role for Farnesoid X Receptor?
    • Clinical, Structural, and Functional Implications of NADPH–Cytochrome P450 Oxidoreductase Deficiency
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  • Physiological Regulation of Drug Transport and Metabolism
  • P450 System Protein-Protein and Protein-Lipid Interactions
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