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SHORT COMMUNICATION

A Null Allele Impairs Function of CYP2C76 Gene in Cynomolgus Monkeys: A Possible Genetic Tool for Generation of a Better Animal Model in Drug Metabolism

Laboratories of Translational Research (Y.U., H.S., T.Ku., G.K., R.N.) and Drug Metabolism (T.Ka.) Graduate School of Pharmaceutical Sciences, Hokkaido University, Hokkaido, Japan; Shin Nippon Biomedical Laboratories, Ltd., Pharmacokinetics and Bioanalysis Center, Wakayama, Japan (Y.U., S.U., K.M., C.N.); and Shin Nippon Biomedical Laboratories, Ltd., Drug Safety Research Laboratories, Kagoshima, Japan (G.K., R.N.)

The monkey CYP2C76 gene does not correspond to any of the human CYP2C genes, and its enzyme is at least partly responsible for the species difference occasionally seen in drug metabolism between monkeys and humans. To establish a line and/or lines of monkeys that are expected to show metabolic patterns highly similar to humans, we set out to find monkeys that lacked CYP2C76 activity. By genetic screening of 73 monkeys and a database search of expressed sequence tags, we found a total of 10 nonsynonymous genetic variants in the coding region of CYP2C76, including a null genotype (c.449TG>A). Some of the variants were differently distributed between two animal groups originating from different geographical regions (Indochina and Indonesia). After screening 170 additional genomic samples, we identified a total of eight animals (six males and two females) that were heterozygous for c.449TG>A, which could be used for establishing a homozygous line. If the homozygotes show drug-metabolizing properties more similar to humans than wild-type monkeys, the homozygotes may serve as a better animal model for drug metabolism. The data presented in this article provide the essential genetic information to perform a successful study by using cynomolgus monkeys and present a possible tool to generate a better animal model for drug metabolism.