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Marmoset cytochrome P450 2D8 in livers and small intestines metabolizes typical human P450 2D6 substrates, metoprolol, bufuralol and dextromethorphan.
Xenobiotica. 2015; 45(9):766-72.X

Abstract

1. Although the New World non-human primate, the common marmoset (Callithrix jacchus), is a potentially useful animal model, comprehensive understanding of drug metabolizing enzymes is insufficient. 2. A cDNA encoding a novel cytochrome P450 (P450) 2D8 was identified in marmosets. The amino acid sequence deduced from P450 2D8 cDNA showed a high sequence identity (83-86%) with other primate P450 2Ds. Phylogenetic analysis showed that marmoset P450 2D8 was closely clustered with human P450 2D6, unlike P450 2Ds of miniature pig, dog, rabbit, guinea pig, mouse or rat. 3. Marmoset P450 2D8 mRNA was predominantly expressed in the liver and small intestine among the tissues types analyzed, whereas marmoset P450 2D6 mRNA was expressed predominantly in the liver where P450 2D protein was detected by immunoblotting. 4. By metabolic assays using marmoset P450 2D8 protein heterologously expressed in Escherichia coli, although P450 2D8 exhibits lower catalytic efficiency compared to marmoset and human P450 2D6 enzymes, P450 2D8 mediated O-demethylations of metoprolol and dextromethorphan and bufuralol 1'-hydroxylation. 5. These results suggest that marmoset P450 2D8 (also expressed in the extrahepatic tissues) has potential roles in drug metabolism in a similar manner to those of human and marmoset P450 2D6.

Authors+Show Affiliations

a Laboratory of Drug Metabolism and Pharmacokinetics , Showa Pharmaceutical University , Machida , Tokyo , Japan .No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

25801057

Citation

Uehara, Shotaro, et al. "Marmoset Cytochrome P450 2D8 in Livers and Small Intestines Metabolizes Typical Human P450 2D6 Substrates, Metoprolol, Bufuralol and Dextromethorphan." Xenobiotica; the Fate of Foreign Compounds in Biological Systems, vol. 45, no. 9, 2015, pp. 766-72.
Uehara S, Uno Y, Hagihira Y, et al. Marmoset cytochrome P450 2D8 in livers and small intestines metabolizes typical human P450 2D6 substrates, metoprolol, bufuralol and dextromethorphan. Xenobiotica. 2015;45(9):766-72.
Uehara, S., Uno, Y., Hagihira, Y., Murayama, N., Shimizu, M., Inoue, T., Sasaki, E., & Yamazaki, H. (2015). Marmoset cytochrome P450 2D8 in livers and small intestines metabolizes typical human P450 2D6 substrates, metoprolol, bufuralol and dextromethorphan. Xenobiotica; the Fate of Foreign Compounds in Biological Systems, 45(9), 766-72. https://doi.org/10.3109/00498254.2015.1019595
Uehara S, et al. Marmoset Cytochrome P450 2D8 in Livers and Small Intestines Metabolizes Typical Human P450 2D6 Substrates, Metoprolol, Bufuralol and Dextromethorphan. Xenobiotica. 2015;45(9):766-72. PubMed PMID: 25801057.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Marmoset cytochrome P450 2D8 in livers and small intestines metabolizes typical human P450 2D6 substrates, metoprolol, bufuralol and dextromethorphan. AU - Uehara,Shotaro, AU - Uno,Yasuhiro, AU - Hagihira,Yuya, AU - Murayama,Norie, AU - Shimizu,Makiko, AU - Inoue,Takashi, AU - Sasaki,Erika, AU - Yamazaki,Hiroshi, Y1 - 2015/07/27/ PY - 2015/3/25/entrez PY - 2015/3/25/pubmed PY - 2016/6/9/medline KW - CYP2D6 KW - CYP2D8 KW - Common marmoset KW - drug oxidation KW - human SP - 766 EP - 72 JF - Xenobiotica; the fate of foreign compounds in biological systems JO - Xenobiotica VL - 45 IS - 9 N2 - 1. Although the New World non-human primate, the common marmoset (Callithrix jacchus), is a potentially useful animal model, comprehensive understanding of drug metabolizing enzymes is insufficient. 2. A cDNA encoding a novel cytochrome P450 (P450) 2D8 was identified in marmosets. The amino acid sequence deduced from P450 2D8 cDNA showed a high sequence identity (83-86%) with other primate P450 2Ds. Phylogenetic analysis showed that marmoset P450 2D8 was closely clustered with human P450 2D6, unlike P450 2Ds of miniature pig, dog, rabbit, guinea pig, mouse or rat. 3. Marmoset P450 2D8 mRNA was predominantly expressed in the liver and small intestine among the tissues types analyzed, whereas marmoset P450 2D6 mRNA was expressed predominantly in the liver where P450 2D protein was detected by immunoblotting. 4. By metabolic assays using marmoset P450 2D8 protein heterologously expressed in Escherichia coli, although P450 2D8 exhibits lower catalytic efficiency compared to marmoset and human P450 2D6 enzymes, P450 2D8 mediated O-demethylations of metoprolol and dextromethorphan and bufuralol 1'-hydroxylation. 5. These results suggest that marmoset P450 2D8 (also expressed in the extrahepatic tissues) has potential roles in drug metabolism in a similar manner to those of human and marmoset P450 2D6. SN - 1366-5928 UR - https://www.unboundmedicine.com/medline/citation/25801057/Marmoset_cytochrome_P450_2D8_in_livers_and_small_intestines_metabolizes_typical_human_P450_2D6_substrates_metoprolol_bufuralol_and_dextromethorphan_ L2 - https://www.tandfonline.com/doi/full/10.3109/00498254.2015.1019595 DB - PRIME DP - Unbound Medicine ER -