PT  - JOURNAL ARTICLE
AU  - Ohura, Kayoko
AU  - Igawa, Yoshiyuki
AU  - Tanaka, Maori
AU  - Matsumoto, Kana
AU  - Kasahara, Akiko
AU  - Wada, Naoya
AU  - Kubota, Kazuishi
AU  - Uno, Yasuhiro
AU  - Imai, Teruko
TI  - Identification and Characterization of a New Carboxylesterase 2 Isozyme, mfCES2C, in the Small Intestine of Cynomolgus Monkeys
AID  - 10.1124/dmd.119.089011
DP  - 2020 Mar 01
TA  - Drug Metabolism and Disposition
PG  - 146--152
VI  - 48
IP  - 3
4099  - http://dmd.aspetjournals.org/content/48/3/146.short
4100  - http://dmd.aspetjournals.org/content/48/3/146.full
SO  - Drug Metab Dispos2020 Mar 01; 48
AB  - In contrast to a single human carboxylesterase 2 (CES2) isozyme (hCE2), three CES2 genes have been identified in cynomolgus monkeys: mfCES2A, mfCES2B, and mfCES2C. Although mfCES2A protein is expressed in several organs, mfCES2B is a pseudogene and the phenotype of the mfCES2C gene has not yet been clarified in tissues. In previous studies, we detected an unidentified esterase in the region of CES2 mobility upon nondenaturing PAGE analysis of monkey intestinal microsomes, which showed immunoreactivity for anti-mfCES2A antibody. The aim of the present study was to identify this unidentified esterase from monkey small intestine. The esterase was separated on nondenaturing PAGE gel and digested in-gel with trypsin. The amino acid sequences of fragmented peptides were analyzed by tandem mass spectrometry. The unidentified esterase was shown to be identical to mfCES2C (XP_015298642.1, predicted from the genome sequence data). mfCES2C consists of 559 amino acid residues and shows approximately 90% homology with mfCES2A (561 amino acid residues). In contrast to the ubiquitous expression of mfCES2A, mfCES2C is only expressed in the small intestine, kidney, and skin. The hydrolytic properties of recombinant mfCES2C, expressed in HEK293 cells, with respect to p-nitrophenyl derivatives, 4-methylumbelliferyl acetate, and irinotecan were similar to those of recombinant mfCES2A. However, mfCES2C showed a hydrolase activity for O-n-valeryl propranolol higher than mfCES2A. It is concluded that the previously unidentified monkey intestinal CES2 is mfCES2C, which shows different hydrolytic properties to mfCES2A, depending on the substrate.SIGNIFICANCE STATEMENT In the present research, we determined that mfCES2C, a novel monkey CES2 isozyme, is expressed in the small intestine and kidney of the cynomolgus monkey. Interestingly, mfCES2C showed a relatively wide substrate specificity for ester-containing compounds. These findings may, in early stages of drug development, support the use of in vitro–to–in vivo extrapolation for the intestinal hydrolysis of ester drugs in the cynomolgus monkey.