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Drug Metabolism and Disposition Fast Forward
First published on July 20, 2005; DOI: 10.1124/dmd.105.005488

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Received for publication May 13, 2005.
Revised July 18, 2005.
Accepted for publication July 19, 2005.

Human CYP2D6 and mouse CYP2Ds: organ distribution in a humanized mouse model

Sharon Miksys 1*, Connie Cheung 2, Frank J. Gonzalez 2, Rachel F. Tyndale 1

1 University of Toronto 2 NCI, NIH

* Address correspondence to: E-mail: s.miksys{at}utoronto.ca

Abstract

Polymorphic cytochrome 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 to the expression of mouse CYP2D enzymes in these organs. In humans, these organs are of interest with respect to CYP-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.


Key words: CYP expression, CYP2D, cytochrome P450 function, extrahepatic cytochrome P450, extrahepatic drug metabolism, intestinal bioavailability, toxicity


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