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Drug Metabolism and Disposition Fast Forward
First published on February 14, 2008; DOI: 10.1124/dmd.107.019349

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Received for publication October 19, 2007.
Revised January 30, 2008.
Accepted for publication February 11, 2008.

Generation of mice transgenic for human CYP2C18 and CYP2C19. Characterization of the sexually dimorphic gene- and enzyme expression

Susanne Lofgren 1, R. Michael Baldwin 2*, Masahiro Hiratsuka 3, Annelie Lindqvist 4, Anne Carlberg 5, Sarah C Sim 5, Meint Schulke 6, Michael Snait 7, Anne Edenro 6, Ronny Fransson-Steen 1, Ylva Terelius 4, Magnus Ingelman-Sundberg 5

1 Safety Assessment Sweden, AstraZeneca R&D Sodertalje, SE-15185 Sodertalje, Sweden 2 Karolinska Institute 3 Dept. of Clinical Pharmacotherapeutics, Tohoku Pharmaceutical University, Japan 4 Medivir AB, P.O. Box 1086, SE-141 22 Huddinge, Sweden 5 Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet 6 AstraZeneca Transgenics & Comparative Genomics (ATCG), AstraZeneca R&D, Molndal; Sweden 7 Cambridge Antibody Technology, Milstein Building Granta Park, Cambridge, CB21 6GH, United Kingdom

* Address correspondence to: E-mail: mike.baldwin{at}ki.se

Abstract

CYP2C19 is an important enzyme for human drug metabolism, and it also participates in the metabolism of endogenous substrates, whereas the CYP2C18 enzyme is not expressed in human liver despite high mRNA expression. Mice transgenic for the human CYP2C18 and CYP2C19 genes were generated. Quantitative mRNA analysis showed CYP2C18 and CYP2C19 transcripts in liver, kidneys and heart to be expressed in a sexually dimorphic manner, with male mice having 2- to 100-fold higher levels. Transcript levels in the small intestine were somewhat higher than liver, but were similar in both sexes. Transgene mRNA expression was much lower in lung and brain and least in the heart. Immunoblotting using an antipeptide antiserum, reactive with human CYP2Cs and mouse CYP2C70, revealed increased immunoreactive protein in liver microsomes from heterozygous transgenic male mice and a concomitant increase in 5'-hydroxylation of R-omeprazole and S mephenytoin intrinsic clearance, consistent with CYP2C19 overexpression. A CYP2C18 specific antiserum showed that this enzyme was not expressed in livers or kidneys from heterozygous transgenic mice, but the antiserum had high affinity for recombinant CYP2C18 expressed in COS-7 cells. It is concluded that i) both the CYP2C18 and CYP2C19 genes are subject to sexually dimorphic regulation in murine liver, kidney and heart, ii) the CYP2C18 protein is not expressed in murine liver or kidney despite high levels of the corresponding mRNA, and iii) this transgenic model might be suitable for studying sex dependent regulation of the human CYP2C genes and possibly serve as an in vivo model for CYP2C19-dependent drug metabolism.


Key words: CYP gene regulation, CYP2C, cytochrome P450, cytochrome P450 regulation, sexual dimorphism, transgenic models




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