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

0090-9556/06/3404-696-701$20.00
DMD 34:696-701, 2006

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

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

Development Research, R&D, Kissei Pharmaceutical Co., Ltd., Nagano, Japan (M.T., Y.I., S.T., T.K., M.N., M.M., J.K., F.S., N.S.); Department of Surgery, Shinshu University School of Medicine, Nagano, Japan (S.O., Y.H., S.M.); Division of Laboratory Animal Research, Research Center for Human and Environmental Sciences, Shinshu University, Nagano, Japan (S.O., A.K., Y.T.); Department of Organ Regeneration, Shinshu University Graduate School of Medicine, Nagano, Japan (E.T.); and Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Kanagawa, Japan (E.T., Y.T.)

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 (P450) 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 P450 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 6ß-hydroxytestosterone (6ß-OHT), 16{alpha}-OHT, 2{alpha}-OHT, and 2ß-OHT in this system, and was not hydroxylated to 15{alpha}-OHT, 7{alpha}-OHT, and 16ß-OHT. This metabolism profile was similar to that of fetal hepatocytes and different from that of adult hepatocytes. Furthermore, pretreatment with phenobarbital resulted in a 2.5- and 2.6-fold increase in the production of 6ß-OHT and 16ß-OHT. Thus, evidence for drug metabolic activities in relation to P450s has been demonstrated in this system. These results in this system would be a stepping stone of the research on the development and differentiation to adult liver.

Address correspondence to: Dr. Yoh-ichi Tagawa, Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, B-51 4259 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501, Japan. E-mail: ytagawa{at}bio.titech.ac.jp






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