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Research ArticleArticle

HUMAN CYP2D6 AND MOUSE CYP2DS: ORGAN DISTRIBUTION IN A HUMANIZED MOUSE MODEL

Sharon L. Miksys, Connie Cheung, Frank J. Gonzalez and Rachel F. Tyndale
Drug Metabolism and Disposition October 2005, 33 (10) 1495-1502; DOI: https://doi.org/10.1124/dmd.105.005488
Sharon L. Miksys
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Connie Cheung
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Frank J. Gonzalez
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Rachel F. Tyndale
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Abstract

Polymorphic cytochrome P450 (P450) 2D6 (CYP2D6) metabolizes several classes of therapeutic drugs, endogenous neurochemicals, and toxins. A CYP2D6-humanized transgenic mouse line was previously developed to model CYP2D6-poor and -extensive metabolizer phenotypes. Human CYP2D6 was detected in the liver, kidney, and intestine of these animals. In this study, we investigated further the cellular expression and relative tissue levels of human CYP2D6 in these transgenic mice in liver, intestine, kidney, and brain. In addition, we compared this with the expression of mouse CYP2D enzymes in these organs. In humans, these organs are of interest with respect to P450-mediated drug metabolism, toxicity, and disease. The expression of human CYP2D6 and mouse CYP2D enzymes in humanized and wild-type mice was quantified by immunoblotting and detected at the cellular level by immunocytochemistry. The cell-specific expression of human CYP2D6 in liver, kidney, and intestine in humanized mice was similar to that reported in humans. The expression patterns of mouse CYP2D proteins were similar to those in humans in liver and kidney but substantially different in intestine. Human CYP2D6 was not detected in brain of transgenic mice. Mouse CYP2D proteins were detected in brain, allowing, for the first time, a direct comparison of CYP2D expression among mouse, rat, and human brain. This transgenic mouse model is useful for investigating CYP2D6-mediated metabolism in liver, kidney, and especially the intestine, where expression patterns demonstrated substantial species differences.

Footnotes

  • This work was funded by Centre for Addiction and Mental Health, Canadian Institutes of Health Research Grant MOP 14173, and Canada Research Chair to R.F.T.

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

  • doi:10.1124/dmd.105.005488.

  • ABBREVIATIONS: P450, cytochrome P450; TBST, Tris-buffered saline Triton-X; BSA, bovine serum albumin; MAB, monoclonal antibody; PAB, polyclonal antibody; PBS, phosphate-buffered saline; NHS, normal horse serum.

    • Received May 12, 2005.
    • Accepted July 19, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 33 (10)
Drug Metabolism and Disposition
Vol. 33, Issue 10
1 Oct 2005
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Research ArticleArticle

HUMAN CYP2D6 AND MOUSE CYP2DS: ORGAN DISTRIBUTION IN A HUMANIZED MOUSE MODEL

Sharon L. Miksys, Connie Cheung, Frank J. Gonzalez and Rachel F. Tyndale
Drug Metabolism and Disposition October 1, 2005, 33 (10) 1495-1502; DOI: https://doi.org/10.1124/dmd.105.005488

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Research ArticleArticle

HUMAN CYP2D6 AND MOUSE CYP2DS: ORGAN DISTRIBUTION IN A HUMANIZED MOUSE MODEL

Sharon L. Miksys, Connie Cheung, Frank J. Gonzalez and Rachel F. Tyndale
Drug Metabolism and Disposition October 1, 2005, 33 (10) 1495-1502; DOI: https://doi.org/10.1124/dmd.105.005488
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