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Molecular Pharmacology

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Research ArticleArticle

Yeast Expressed Cytochrome P450 2D6 (CYP2D6) Exposed on the External Face of Plasma Membrane Is Functionally Competent

Jacqueline Loeper, Bénédicte Louérat-Oriou, Catherine Duport and Denis Pompon
Molecular Pharmacology July 1998, 54 (1) 8-13; DOI: https://doi.org/10.1124/mol.54.1.8
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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Bénédicte Louérat-Oriou
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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Catherine Duport
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

CYP2D6, a xenobiotic metabolizing cytochrome P450 (P450), was found to be present in significant amount on the outer face of cell plasma membrane in addition to the regular microsomal location. Present work demonstrates that this external P450 is catalytically competent and that activity is supported by NADPH-P450 reductase present on the inner face of plasma membrane. Purified plasma membranes from yeast expressing CYP2D6 sustained NADPH- and cumene hydroperoxide-dependent dextromethorphan demethylation and NADPH-cytochrome c activity confirming previous observations in human hepatocytes. CYP2D6 found on the outside of plasma membrane (by differential immuno-inhibition and acidic shift assays on transformed spheroplasts) was catalytically competent at the cell surface for NADPH-supported activities. Anti-yeast P450-reductase antibodies inhibited neither CYP2D6 nor P450-reductase activities upon incubation with intact spheroplasts. In contrast, both activities were inhibited on isolated plasma membrane fragments. This highly suggested a cytosolic-orientation of the plasma membrane P450-reductase. This finding was confirmed by immunostaining in confocal microscopy. Finally, gene deletion of P450-reductase caused a complete loss of plasma membrane NADPH-supported CYP2D6 activity, which suggests that the reductase participates to some degree in the transmembrane electron transfer chain. This work illustrates that the outside-exposed plasma membrane CYP2D6 is active and may play an important metabolic role.

Footnotes

    • Received January 23, 1998.
    • Accepted March 17, 1998.
  • 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: 54 (1)
Molecular Pharmacology
Vol. 54, Issue 1
1 Jul 1998
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Research ArticleArticle

Yeast Expressed Cytochrome P450 2D6 (CYP2D6) Exposed on the External Face of Plasma Membrane Is Functionally Competent

Jacqueline Loeper, Bénédicte Louérat-Oriou, Catherine Duport and Denis Pompon
Molecular Pharmacology July 1, 1998, 54 (1) 8-13; DOI: https://doi.org/10.1124/mol.54.1.8

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Research ArticleArticle

Yeast Expressed Cytochrome P450 2D6 (CYP2D6) Exposed on the External Face of Plasma Membrane Is Functionally Competent

Jacqueline Loeper, Bénédicte Louérat-Oriou, Catherine Duport and Denis Pompon
Molecular Pharmacology July 1, 1998, 54 (1) 8-13; DOI: https://doi.org/10.1124/mol.54.1.8
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