title: Genetic polymorphism of cynomolgus and rhesus macaque CYP2C9.
abstract: Cynomolgus and rhesus macaques are non-human primate species widely used in drug metabolism studies. Cynomolgus CYP2C9 (formerly known as CYP2C43) is predominantly expressed in liver and encodes a drug-metabolizing enzyme that metabolizes human CYP2C substrates such as S-mephenytoin and progesterone. In addition, cynomolgus CYP2C9 also metabolizes caffeine, resulting in the formation of the metabolite that is not generated efficiently in humans. Genetic variants of human CYP2C genes account for the inter-individual variability in drug metabolism: however, CYP2C9 variants have not been found in macaques. To see if CYP2C9 is polymorphic in macaques, in this study, CYP2C9 was re-sequenced in 78 cynomolgus and 36 rhesus macaques. A total of 27 non-synonymous variants were found, among which 4 were located in substrate recognition sites, the domain important for protein function. Thirteen and seven variants were unique to cynomolgus and rhesus macaques, respectively. This study revealed the polymorphic nature of cynomolgus and rhesus CYP2C9, similar to human CYP2C genes, by identification of numerous genetic variants including non-synonymous variants.
authors.affiliation: Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., 16-1 Minami Akasaka, Kainan, Wakayama, Japan. Electronic address: uno-yasuhiro@snbl.co.jp.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Uno
authors.affiliation: Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., 16-1 Minami Akasaka, Kainan, Wakayama, Japan; Drug Safety Research Center, Shin Nippon Biomedical Laboratories, Ltd., Kagoshima, Kagoshima, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Matsushita
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, Japan.
authors.forename: Norie
authors.initials: N
authors.lastname: Murayama
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamazaki
mesh_terms: D000818:Animals; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics*; D004247:DNA / Q000097:blood / Q000235:genetics; D004926:Escherichia coli / Q000235:genetics; D005091:Exons / Q000235:genetics; D008252:Macaca fascicularis; D008253:Macaca mulatta; D004364:Pharmaceutical Preparations / Q000378:metabolism; D011110:Polymorphism, Genetic; D013045:Species Specificity; D013379:Substrate Specificity
chemical_list: D004364:Pharmaceutical Preparations; D004247:DNA; D065729:Cytochrome P-450 CYP2C9
keywords: Cytochrome P450; Genetic polymorphisms; Metabolic activity; Monkey