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Drug Metabolism & Disposition

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OtherShort Communication

A Natural Variant of the Heme-Binding Signature (R441C) Resulting in Complete Loss of Function of CYP2D6

Kathrin Klein, Stephan Tatzel, Sebastian Raimundo, Tanja Saussele, Elisabeth Hustert, Jürgen Pleiss, Michel Eichelbaum and Ulrich M. Zanger
Drug Metabolism and Disposition August 2007, 35 (8) 1247-1250; DOI: https://doi.org/10.1124/dmd.107.015149
Kathrin Klein
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Stephan Tatzel
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Sebastian Raimundo
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Tanja Saussele
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Elisabeth Hustert
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Jürgen Pleiss
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Michel Eichelbaum
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Ulrich M. Zanger
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Abstract

A new variant allele CYP2D6*62 (g.4044C>T; R441C) of the drug-metabolizing cytochrome P450 (P450) CYP2D6 was identified in a person with reduced sparteine oxidation phenotype, which was unexpected based on a genetic CYP2D6*1A/*41 background. The recombinantly expressed variant protein had no activity toward propafenone as a result of missing heme incorporation. Sequence alignment revealed that the positively charged R441 residue is part of the heme-binding signature but not strictly conserved among all the P450s. A compilation of described P450 monooxygenase variants revealed that other enzymes can functionally tolerate even nonconservative amino acid changes at the corresponding position (i.e., the invariant cysteine 2). This suggests that heme binding in mammalian P450s depends not only on the integrity of the heme-binding signature but also on other family- and subfamily-specific sequence determinants.

Footnotes

  • This work was supported by the German Federal Ministry of Education and Research (Project 0313080D&A).

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.107.015149.

  • ABBREVIATIONS: P450, cytochrome P450; PM, poor metabolizer; PCR, polymerase chain reaction; MRS, sparteine oxidation metabolic ratio.

  • ↵ Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

    • Received February 14, 2007.
    • Revision received April 23, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 35 (8)
Drug Metabolism and Disposition
Vol. 35, Issue 8
1 Aug 2007
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OtherShort Communication

A Natural Variant of the Heme-Binding Signature (R441C) Resulting in Complete Loss of Function of CYP2D6

Kathrin Klein, Stephan Tatzel, Sebastian Raimundo, Tanja Saussele, Elisabeth Hustert, Jürgen Pleiss, Michel Eichelbaum and Ulrich M. Zanger
Drug Metabolism and Disposition August 1, 2007, 35 (8) 1247-1250; DOI: https://doi.org/10.1124/dmd.107.015149

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OtherShort Communication

A Natural Variant of the Heme-Binding Signature (R441C) Resulting in Complete Loss of Function of CYP2D6

Kathrin Klein, Stephan Tatzel, Sebastian Raimundo, Tanja Saussele, Elisabeth Hustert, Jürgen Pleiss, Michel Eichelbaum and Ulrich M. Zanger
Drug Metabolism and Disposition August 1, 2007, 35 (8) 1247-1250; DOI: https://doi.org/10.1124/dmd.107.015149
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