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Drug Metabolism and Disposition Fast Forward
First published on January 13, 2006; DOI: 10.1124/dmd.105.007674

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Received for publication October 5, 2005.
Revised January 3, 2006.
Accepted for publication January 6, 2006.

CHARACTERIZATION OF CYTOCHROME P450 EXPRESSION IN MURINE EMBRYONIC STEM CELL-DERIVED HEPATIC TISSUE SYSTEM

Masaru Tsutsui 1, Shinichiro Ogawa 2, Yoichi Inada 1, Eisuke Tomioka 3, Akiko Kamiyoshi 4, Satoru Tanaka 1, Tomoyuki Kishida 1, Masahiko Nishiyama 1, Makoto Murakami 1, Junji Kuroda 1, Yasuhiko Hashikura 2, Shinichi Miyagawa 2, Fumiyasu Satoh 1, Nobuo Shibata 1, Yoh-ichi Tagawa 3*

1 Kissei Pharmaceutical Co., Ltd. 2 Shinshu University School of Medicine 3 Tokyo Institute of Technology 4 Shinshu University

* Address correspondence to: E-mail: ytagawa{at}bio.titech.ac.jp

Abstract

An in vitro system for liver organogenesis from murine embryonic stem (ES) cells has been recently established. This system is expected to be applied to the development of a new drug metabolism assay system that uses ES cells as a substitute for animal experiments. The objective of this study was to elucidate the drug metabolism profiles of the murine ES cell-derived hepatic tissue system compared with those of primary cultures of murine adult and fetal hepatocytes. The expression of the genes of the cytochrome P450 (CYP) family, such as Cyp2a5, Cyp2b10, Cyp2c29, Cyp2d9, Cyp3a11, and Cyp7a1 was observed in the murine ES cell-derived hepatic tissue system at 16 days and 18 days after plating (A16 and A18). To investigate the activities of these Cyp family enzymes in the murine ES cell-derived hepatic tissue system at A16 and A18, testosterone metabolism in this system was analyzed. Testosterone was hydroxylated to 6{beta}-hydroxytestosterone (6{beta}-OHT), 16{alpha}-OHT, 2{alpha}-OHT, and 2{beta}-OHT in this system, and was not hydroxylated to 15{alpha}-OHT, 7{alpha}-OHT, and 16{beta}-OHT. This metabolism profile was similar to fetal hepatocytes, and different from adult hepatocytes. Further, pretreatment with phenobarbital resulted in a 2.5 and 2.6-fold increase in the production of 6{beta}-OHT and 16{beta}-OHT. Thus, evidence for drug metabolic activities in relation to Cyps has been demonstrated in this system. These results in this system would be a steppingstone of the research on the development and differentiation to adult liver.


Key words: cytochrome P450, drug discovery, hepatocytes, HPLC, induction




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