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Drug Metabolism and Disposition Fast Forward
First published on June 2, 2005; DOI: 10.1124/dmd.105.005157

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Received for publication April 13, 2005.
Revised May 27, 2005.
Accepted for publication June 1, 2005.

EXPRESSION OF HUMAN PHASE II ENZYMES IN CHIMERIC MICE WITH HUMANIZED LIVER

Miki Katoh 1, Tomohito Matsui 1, Hirotoshi Okumura 1, Miki Nakajima 1, Masuhiro Nishimura 2, Shinsaku Naito 2, Chise Tateno 3, Katsutoshi Yoshizato 4, Tsuyoshi Yokoi 1*

1 Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University 2 Otsuka Pharmaceutical Factory Inc. 3 Hiroshima Prefectural Institute of Industrial Science and Technology 4 Graduate School of Science, Hiroshima University

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

Abstract

We clarified that major human cytochrome P450 (P450) enzymes were expressed in a chimeric mouse line established recently in Japan, in which the liver could be replaced by more than 80% with human hepatocytes. In this study, we investigated major human phase II enzymes such as UDP glucuronosyltransferase (UGT), sulfotransferase (SULT), N-acetyltransferase (NAT), and glutathione S-transferase (GST) in the livers of chimeric mice by mRNA, protein, and enzyme activity using reverse-transcription-polymerase chain reaction, Western blot analysis, and high-performance liquid chromatography, respectively. Human UGT, SULT, NAT, and GST mRNA were expressed in the liver of the chimeric mice, and UGT2B7, SULT1E, SULT2A1, and GSTA1 proteins could be detected. The expression of mRNA and protein were correlated with the human albumin (hAlb) concentration in mouse blood, the replacement of which by human hepatocytes could be estimated by the hAlb concentration in the blood of the chimeric mice, because the chimeric mice produce human albumin. The enzyme activities such as morphine 6-glucuronosyltransferase activity and estrone 3-sulfotransferase activity, activities that are specific to human but not to murine, were increased in a hAlb concentration-dependent manner. The chimeric mice with humanized liver with nearly 90% replacement by human hepatocytes demonstrated almost the same protein contents of human phase II enzymes and enzyme activities as those of the donor. In conclusion, the chimeric mice exhibited a similarly efficient capacity of drug conjugation as humans. These chimeric mice expressed human phase II enzymes as well as P450s, suggesting that they could be a useful animal model in drug development.


Key words: acetyltransferases, glutathione transferases, phase II drug metabolism, sulfotransferases, UDP glucuronyltransferases


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