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Substrate Selectivities and Catalytic Activities of Marmoset Liver Cytochrome P450 2A6 Differed from Those of Human P450 2A6.
Drug Metab Dispos. 2015 Jul; 43(7):969-76.DM

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.

Authors+Show Affiliations

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.).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.).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.).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.).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.) hyamazak@ac.shoyaku.ac.jp.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25858611

Citation

Uehara, Shotaro, et al. "Substrate Selectivities and Catalytic Activities of Marmoset Liver Cytochrome P450 2A6 Differed From Those of Human P450 2A6." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 43, no. 7, 2015, pp. 969-76.
Uehara S, Uno Y, Inoue T, et al. Substrate Selectivities and Catalytic Activities of Marmoset Liver Cytochrome P450 2A6 Differed from Those of Human P450 2A6. Drug Metab Dispos. 2015;43(7):969-76.
Uehara, S., Uno, Y., Inoue, T., Sasaki, E., & Yamazaki, H. (2015). Substrate Selectivities and Catalytic Activities of Marmoset Liver Cytochrome P450 2A6 Differed from Those of Human P450 2A6. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 43(7), 969-76. https://doi.org/10.1124/dmd.115.063909
Uehara S, et al. Substrate Selectivities and Catalytic Activities of Marmoset Liver Cytochrome P450 2A6 Differed From Those of Human P450 2A6. Drug Metab Dispos. 2015;43(7):969-76. PubMed PMID: 25858611.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Substrate Selectivities and Catalytic Activities of Marmoset Liver Cytochrome P450 2A6 Differed from Those of Human P450 2A6. AU - Uehara,Shotaro, AU - Uno,Yasuhiro, AU - Inoue,Takashi, AU - Sasaki,Erika, AU - Yamazaki,Hiroshi, Y1 - 2015/04/09/ PY - 2015/02/18/received PY - 2015/04/09/accepted PY - 2015/4/11/entrez PY - 2015/4/11/pubmed PY - 2016/2/18/medline SP - 969 EP - 76 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 43 IS - 7 N2 - 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. SN - 1521-009X UR - https://www.unboundmedicine.com/medline/citation/25858611/Substrate_Selectivities_and_Catalytic_Activities_of_Marmoset_Liver_Cytochrome_P450_2A6_Differed_from_Those_of_Human_P450_2A6_ DB - PRIME DP - Unbound Medicine ER -