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Research ArticleArticle

Topology Inversion of CYP2D6 in the Endoplasmic Reticulum Is Not Required for Plasma Membrane Transport

Jacqueline Loeper, Annie Le Berre and Denis Pompon
Molecular Pharmacology March 1998, 53 (3) 408-414; DOI: https://doi.org/10.1124/mol.53.3.408
Jacqueline Loeper
Centre de Génétique Moléculaire du Centre National de la Recherche Scientifique, Laboratoire propre associéà l’Université Pierre et Marie Curie, F91198 Gif-sur-Yvette Cedex, France
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Annie Le Berre
Centre de Génétique Moléculaire du Centre National de la Recherche Scientifique, Laboratoire propre associéà l’Université Pierre et Marie Curie, F91198 Gif-sur-Yvette Cedex, France
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Denis Pompon
Centre de Génétique Moléculaire du Centre National de la Recherche Scientifique, Laboratoire propre associéà l’Université Pierre et Marie Curie, F91198 Gif-sur-Yvette Cedex, France
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Abstract

The presence of CYP2D6 at the surface of isolated rat and human hepatocytes and its recognition by autoantibodies were reported recently. We wondered whether the unexpected outside orientation at the plasma membrane could be related to topological inversion (luminal-oriented form) of cytochrome P450 in the endoplasmic reticulum. To examine the potential role of cDNA polymorphism, a CYP2D6 variant carrying three positive charges at the amino terminus (2D6ext) was constructed and expressed in yeast. Immunoblotting, flow cytometry, and electron microscopy showed that wild-type CYP2D6 expressed in yeast was present on the outer face of the cell plasma membrane in addition to the regular microsomal location. This location reproduces the hepatocyte situation. 2D6ext expressed in yeast and COS7 cells seemed to be partially N-glycosylated and was located at the plasma membrane surface. Nevertheless, the glycosylated form was not enriched in the plasma membranes compared with microsomes. The relationship between CYP2D6 and 2D6ext topologies and catalytic competence was tested. Cumene hydroperoxide-dependent dextromethorphan demethylation was performed on microsomal vesicles after combined proteolysis and immunoinhibition experiments. CYP2D6 activity was completely abolished, whereas the glycosylated and luminal-oriented fraction of 2D6ext remained active. This suggests that a luminal-oriented glycosylated form is not involved in cytochrome P450 transport to the plasma membrane. Yeast thus reproduces the unusual CYP2D6 plasma membrane location and orientation, which do not require sequence alteration, glycosylation, or even an inverted endoluminal orientation.

Footnotes

    • Received July 21, 1997.
    • Accepted November 20, 1997.
  • Send reprint requests to: Jacqueline Loeper, Pharm.D., Ph.D., Centre de Génétique Moléculaire du CNRS, F91198 Gif-sur-Yvette Cedex, France. E-mail: loeper{at}cgm.cnrs-gif.fr

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Molecular Pharmacology: 53 (3)
Molecular Pharmacology
Vol. 53, Issue 3
1 Mar 1998
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Research ArticleArticle

Topology Inversion of CYP2D6 in the Endoplasmic Reticulum Is Not Required for Plasma Membrane Transport

Jacqueline Loeper, Annie Le Berre and Denis Pompon
Molecular Pharmacology March 1, 1998, 53 (3) 408-414; DOI: https://doi.org/10.1124/mol.53.3.408

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Research ArticleArticle

Topology Inversion of CYP2D6 in the Endoplasmic Reticulum Is Not Required for Plasma Membrane Transport

Jacqueline Loeper, Annie Le Berre and Denis Pompon
Molecular Pharmacology March 1, 1998, 53 (3) 408-414; DOI: https://doi.org/10.1124/mol.53.3.408
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