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CYP2D44 polymorphisms in cynomolgus and rhesus macaques

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Abstract

Macaques, including cynomolgus and rhesus macaques, are important animal species used in drug metabolism studies. CYP2D44 is expressed in cynomolgus macaque liver and encodes a functional drug metabolizing enzyme, metabolizing typical human CYP2D substrates such as bufuralol and dextromethorphan. CYP2D44 is highly homologous to human CYP2D6 that is known to be polymorphic with a large inter-individual variation in metabolic activities, however, genetic polymorphisms have not been investigated in macaque CYP2D44. In the present study, screening of 78 cynomolgus and 40 rhesus macaques found a total of 67 variants, including 64 non-synonymous variants, 1 nonsense mutation, and 2 frameshift mutations, and 1 gene conversion, of which 14, 19, and 15 variants were unique to Indochinese cynomolgus macaques, Indonesian cynomolgus macaques, and Chinese rhesus macaques, respectively. Eleven of the 64 non-synonymous variants were located in substrate recognition sites, the regions important for protein function. By site-directed mutagenesis and metabolic assays, S175N, V185L, A235G, R242G, R245K, and N337D showed substantially decreased activity in bufuralol 1′-hydroxylation as compared with wild-type proteins. Moreover, two null alleles (c.128T>del and c.664G>T) were found in Indonesian cynomolgus macaques, but not in Indochinese cynomolgus macaques or Chinese rhesus macaques. These results suggest that genetic polymorphisms might account for the variability of CYP2D44-dependent metabolism in macaques.

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Acknowledgments

We greatly thank Mr. Masahiro Utoh for his support of this work, and Mr. Lance Bell for his advice on English writing.

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Authors and Affiliations

  1. Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., 16-1 Minami Akasaka, Kainan, Wakayama, 642-0017, Japan

    Yasuhiro Uno, Shotaro Uehara & Sakae Kohara

  2. Department of Population Genetics, National Institute of Genetics, Mishima, Shizuoka, Japan

    Naoki Osada

  3. Department of Genetics, Graduate University for Advanced Studies (SOKENDAI), Mishima, Japan

    Naoki Osada

  4. Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, Japan

    Shotaro Uehara, Norie Murayama & Hiroshi Yamazaki

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  1. Yasuhiro Uno
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  2. Shotaro Uehara
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  3. Sakae Kohara
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  4. Naoki Osada
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  5. Norie Murayama
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  6. Hiroshi Yamazaki
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Correspondence to Yasuhiro Uno.

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Uno, Y., Uehara, S., Kohara, S. et al. CYP2D44 polymorphisms in cynomolgus and rhesus macaques. Mol Biol Rep 42, 1149–1155 (2015). https://doi.org/10.1007/s11033-015-3863-0

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  • DOI: https://doi.org/10.1007/s11033-015-3863-0

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