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Drug Metabolism and Disposition Fast Forward
First published on March 15, 2005; DOI: 10.1124/dmd.104.002600

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Received for publication October 6, 2004.
Revised March 9, 2005.
Accepted for publication March 10, 2005.

IN VIVO INDUCTION OF HUMAN CYTOCHROME P450 ENZYMES EXPRESSED IN CHIMERIC MICE WITH HUMANIZED LIVER

Miki Katoh 1, Tomohito Matsui 1, Miki Nakajima 1, Chise Tateno 2, Yoshinori Soeno 3, Toru Horie 3, Kazuhide Iwasaki 4, Katsutoshi Yoshizato 5, Tsuyoshi Yokoi 1*

1 Kanazawa University, Kanazawa, Japan. 2 Hiroshima Prefectural Institute of Industrial Science and Technology, CLUSTER, Hiroshima, Japan. 3 PhenixBio, Co., Ltd. 4 Pfizer Japan, Ltd. 5 Graduate School of Science, Hiroshima University, Hiroshima, Japan.

* Address correspondence to: E-mail: tyokoi{at}kenroku.kanazawa-u.ac.jp

Abstract

The induction and inhibition of human cytochrome P450 enzymes (CYPs) are responsible for drug interactions clinically. Although the induction of CYPs is investigated using human hepatocytes in the drug development process, there are some disadvantages such as the decline of the enzyme activity during culture. In the present study, we examined the in vivo induction potency in chimeric mice with humanized liver, which was recently established in Japan to clarify whether this chimeric mouse model would be more suitable for human induction studies. Rifampicin and 3-methylcholanthrene (3-MC) were used in vivo as typical CYP inducers in the chimeric mice. The expression levels of human CYP3A4 mRNA and CYP3A4 protein and dexamethasone 6-hydroxylase activity, specific for human CYP3A4, were increased 8- to 22-fold, 3- to 10-fold, and 5- to 12-fold, respectively, by the treatment with rifampicin. In addition, the expression levels of human CYP1A2 mRNA and CYP1A2 protein were also increased 2- to 9-fold and 5-fold, respectively, by the treatment with 3-MC. Although other human CYPs are expressed in the chimeric mice, there were few effects by the treatment of rifampicin and 3-MC on the mRNA, protein, and enzyme activity of those CYPs. It was demonstrated that human CYPs expressed in the chimeric mice with humanized liver were induced by rifampicin and 3-MC. This chimeric mouse model may be a useful animal model to estimate and predict the in vivo induction of CYPs in humans.


Key words: CYP induction, human CYP enzymes


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