title: CYP2D44 polymorphisms in cynomolgus and rhesus macaques.
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.
authors: Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., 16-1 Minami Akasaka, Kainan, Wakayama, 642-0017, Japan, uno-yasuhiro@snbl.co.jp.
authors: Yasuhiro
authors: Y
authors: Uno
authors: Shotaro
authors: S
authors: Uehara
authors: Sakae
authors: S
authors: Kohara
authors: Naoki
authors: N
authors: Osada
authors: Norie
authors: N
authors: Murayama
authors: Hiroshi
authors: H
authors: Yamazaki
mesh_terms: D000818:Animals; D001711:Biotransformation; D019389:Cytochrome P-450 CYP2D6 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D003915:Dextromethorphan / Q000378:metabolism; D004983:Ethanolamines / Q000378:metabolism; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D006900:Hydroxylation; D008099:Liver / Q000201:enzymology*; D008252:Macaca fascicularis / Q000235:genetics* / Q000378:metabolism; D008253:Macaca mulatta / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D011110:Polymorphism, Genetic; D017386:Sequence Homology, Amino Acid
chemical_list: D004983:Ethanolamines; D003915:Dextromethorphan; C010831:bufuralol; D003577:Cytochrome P-450 Enzyme System; D019389:Cytochrome P-450 CYP2D6