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Molecular Cloning, Tissue Distribution, and Functional Characterization of Marmoset Cytochrome P450 1A1, 1A2, and 1B1.
Drug Metab Dispos. 2016 Jan; 44(1):8-15.DM

Abstract

The common marmoset (Callithrix jacchus), a New World monkey, has potential to be an animal model for drug metabolism studies. In this study, we identified and characterized cytochrome P450 (P450) 1A1 and 1B1 in addition to the known P450 1A2 in marmosets. Marmoset P450 1A1 and 1B1 cDNA contained open reading frames encoding 512 and 543 amino acids, respectively, with high sequence identities (90%-93%) to other primate P450 1A1s and 1B1s. A phylogenetic tree based on amino acid sequences showed close evolutionary relationships among marmoset, macaque, and human P450 1A and 1B enzymes. By mRNA quantification and immunoblot analyses in five marmoset tissues, P450 1A1 was mainly expressed in lungs and small intestines, and P450 1A2 was expressed predominantly in livers. In contrast, P450 1B1 was expressed in all tissues tested. Marmoset P450 1A1, 1A2, and 1B1 heterologously expressed in Escherichia coli catalyzed 7-ethoxyresorufin O-deethylation, 7-ethoxycoumarin O-deethylation, and phenacetin O-deethylation, similar to those of humans and cynomolgus monkeys. Notably, marmoset P450 1A1 and 1A2 more efficiently catalyzed 7-ethoxyresorufin O-deethylation than those of the human homologs, but were comparable to those of the cynomolgus monkey homologs. Additionally, marmoset P450 1B1 preferentially catalyzed estradiol 4-hydroxylation; however, rat P450 1B1 more favorably catalyzed estradiol 2-hydroxylation, indicating that the estradiol hydroxylation specificity of marmoset P450 1B1 was similar to those of human and cynomolgus monkey P450 1B1. These results indicated that marmoset P450 1A and 1B enzymes had functional characteristics similar to those of humans and cynomolgus monkeys, suggesting that P450 1A and 1B-dependent metabolism was similar among marmosets, cynomolgus monkeys, and humans.

Authors

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Pub Type(s)

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

Language

eng

PubMed ID

26502772

Citation

Uehara, Shotaro, et al. "Molecular Cloning, Tissue Distribution, and Functional Characterization of Marmoset Cytochrome P450 1A1, 1A2, and 1B1." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 44, no. 1, 2016, pp. 8-15.
Uehara S, Uno Y, Inoue T, et al. Molecular Cloning, Tissue Distribution, and Functional Characterization of Marmoset Cytochrome P450 1A1, 1A2, and 1B1. Drug Metab Dispos. 2016;44(1):8-15.
Uehara, S., Uno, Y., Inoue, T., Sasaki, E., & Yamazaki, H. (2016). Molecular Cloning, Tissue Distribution, and Functional Characterization of Marmoset Cytochrome P450 1A1, 1A2, and 1B1. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 44(1), 8-15. https://doi.org/10.1124/dmd.115.067561
Uehara S, et al. Molecular Cloning, Tissue Distribution, and Functional Characterization of Marmoset Cytochrome P450 1A1, 1A2, and 1B1. Drug Metab Dispos. 2016;44(1):8-15. PubMed PMID: 26502772.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular Cloning, Tissue Distribution, and Functional Characterization of Marmoset Cytochrome P450 1A1, 1A2, and 1B1. AU - Uehara,Shotaro, AU - Uno,Yasuhiro, AU - Inoue,Takashi, AU - Sasaki,Erika, AU - Yamazaki,Hiroshi, Y1 - 2015/10/26/ PY - 2015/10/01/received PY - 2015/10/23/accepted PY - 2015/10/28/entrez PY - 2015/10/28/pubmed PY - 2016/9/14/medline SP - 8 EP - 15 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 44 IS - 1 N2 - The common marmoset (Callithrix jacchus), a New World monkey, has potential to be an animal model for drug metabolism studies. In this study, we identified and characterized cytochrome P450 (P450) 1A1 and 1B1 in addition to the known P450 1A2 in marmosets. Marmoset P450 1A1 and 1B1 cDNA contained open reading frames encoding 512 and 543 amino acids, respectively, with high sequence identities (90%-93%) to other primate P450 1A1s and 1B1s. A phylogenetic tree based on amino acid sequences showed close evolutionary relationships among marmoset, macaque, and human P450 1A and 1B enzymes. By mRNA quantification and immunoblot analyses in five marmoset tissues, P450 1A1 was mainly expressed in lungs and small intestines, and P450 1A2 was expressed predominantly in livers. In contrast, P450 1B1 was expressed in all tissues tested. Marmoset P450 1A1, 1A2, and 1B1 heterologously expressed in Escherichia coli catalyzed 7-ethoxyresorufin O-deethylation, 7-ethoxycoumarin O-deethylation, and phenacetin O-deethylation, similar to those of humans and cynomolgus monkeys. Notably, marmoset P450 1A1 and 1A2 more efficiently catalyzed 7-ethoxyresorufin O-deethylation than those of the human homologs, but were comparable to those of the cynomolgus monkey homologs. Additionally, marmoset P450 1B1 preferentially catalyzed estradiol 4-hydroxylation; however, rat P450 1B1 more favorably catalyzed estradiol 2-hydroxylation, indicating that the estradiol hydroxylation specificity of marmoset P450 1B1 was similar to those of human and cynomolgus monkey P450 1B1. These results indicated that marmoset P450 1A and 1B enzymes had functional characteristics similar to those of humans and cynomolgus monkeys, suggesting that P450 1A and 1B-dependent metabolism was similar among marmosets, cynomolgus monkeys, and humans. SN - 1521-009X UR - https://www.unboundmedicine.com/medline/citation/26502772/Molecular_Cloning_Tissue_Distribution_and_Functional_Characterization_of_Marmoset_Cytochrome_P450_1A1_1A2_and_1B1_ DB - PRIME DP - Unbound Medicine ER -