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Research ArticleArticle

Substrate Selectivities and Catalytic Activities of Marmoset Liver Cytochrome P450 2A6 Differed from Those of Human P450 2A6

Shotaro Uehara, Yasuhiro Uno, Takashi Inoue, Erika Sasaki and Hiroshi Yamazaki
Drug Metabolism and Disposition July 2015, 43 (7) 969-976; DOI: https://doi.org/10.1124/dmd.115.063909
Shotaro Uehara
Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, Japan (S.U., H.Y.); Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Kainan, Wakayama, Japan (Y.U.); Department of Applied Developmental Biology, Central Institute for Experimental Animals, Kawasaki, Japan (T.I., E.S.); and Keio Advanced Research Center, Keio University, Minato-ku, Tokyo, Japan (E.S.)
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Yasuhiro Uno
Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, Japan (S.U., H.Y.); Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Kainan, Wakayama, Japan (Y.U.); Department of Applied Developmental Biology, Central Institute for Experimental Animals, Kawasaki, Japan (T.I., E.S.); and Keio Advanced Research Center, Keio University, Minato-ku, Tokyo, Japan (E.S.)
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Takashi Inoue
Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, Japan (S.U., H.Y.); Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Kainan, Wakayama, Japan (Y.U.); Department of Applied Developmental Biology, Central Institute for Experimental Animals, Kawasaki, Japan (T.I., E.S.); and Keio Advanced Research Center, Keio University, Minato-ku, Tokyo, Japan (E.S.)
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Erika Sasaki
Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, Japan (S.U., H.Y.); Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Kainan, Wakayama, Japan (Y.U.); Department of Applied Developmental Biology, Central Institute for Experimental Animals, Kawasaki, Japan (T.I., E.S.); and Keio Advanced Research Center, Keio University, Minato-ku, Tokyo, Japan (E.S.)
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Hiroshi Yamazaki
Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, Japan (S.U., H.Y.); Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Kainan, Wakayama, Japan (Y.U.); Department of Applied Developmental Biology, Central Institute for Experimental Animals, Kawasaki, Japan (T.I., E.S.); and Keio Advanced Research Center, Keio University, Minato-ku, Tokyo, Japan (E.S.)
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Abstract

The common marmoset (Callithrix jacchus), a New World primate species, is potentially a useful animal model for preclinical studies in drug development. However, cytochrome P450 (P450) enzymes have not been fully identified and characterized in marmosets. In this study, we identified P450 2A6 cDNA with the sequence highly identical (91–94%) to human P450 2A6, 2A7, and 2A13 cDNA and cynomolgus monkey P450 2A23, 2A24, and 2A26 cDNA. Among the tissue types examined, marmoset P450 2A6 mRNA was most abundantly expressed in livers where P450 2A6 protein was also detected by immunoblotting. Phylogenetic analysis showed that marmoset P450 2A6 was more closely clustered with human and cynomolgus monkey P450 2As than P450 2As of dog, rat, and mouse (the species also used in drug metabolism). Marmoset P450 2A6 heterologously expressed in Escherichia coli membranes efficiently catalyzed 7-ethoxycoumarin O-deethylation, similar to human P450 2A6 and 2A13 and cynomolgus monkey P450 2A23, 2A24, and 2A26, but much less effectively coumarin 7-hydroxylation, showing some difference as well. Interestingly, marmoset P450 2A6 and cynomolgus monkey P450 2A23 catalyzed phenacetin O-deethylation, which is catalyzed by human P450 1A2 and 2A13, but not by P450 2A6. Marmoset P450 2A6 also exhibited catalytic activity toward testosterone by the multiple sites, but not rat P450 2A-specific testosterone 7α-hydroxylation activity. These results indicated that marmoset P450 2A6 had functional characteristics different from those of human and cynomolgus monkey P450 2As in terms of partially different substrate specificities and catalytic activities, indicating its importance of further studies for P450 2A-dependent drug metabolism in marmosets.

Footnotes

    • Received February 18, 2015.
    • Accepted April 9, 2015.
  • S.U. and Y.U. equally contributed to this work.

  • This work was supported in part by Grant-in-Aid for Scientific Research and also resulted from “Construction of System for Spread of Primate Model Animals” under the Strategic Research Program for Brain Sciences of the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

  • dx.doi.org/10.1124/dmd.115.063909.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (7)
Drug Metabolism and Disposition
Vol. 43, Issue 7
1 Jul 2015
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Research ArticleArticle

Cloning and Characterization of Marmoset P450 2A6

Shotaro Uehara, Yasuhiro Uno, Takashi Inoue, Erika Sasaki and Hiroshi Yamazaki
Drug Metabolism and Disposition July 1, 2015, 43 (7) 969-976; DOI: https://doi.org/10.1124/dmd.115.063909

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Research ArticleArticle

Cloning and Characterization of Marmoset P450 2A6

Shotaro Uehara, Yasuhiro Uno, Takashi Inoue, Erika Sasaki and Hiroshi Yamazaki
Drug Metabolism and Disposition July 1, 2015, 43 (7) 969-976; DOI: https://doi.org/10.1124/dmd.115.063909
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