Genetic variants of cytochrome P450 2C21 identified by screening 6344 dogs influenced oxidations of the probe drug omeprazole

Abstract

The cytochromes P450 (P450s or CYPs) are essential drug-metabolizing enzymes. In humans, the variability in metabolic activity is partly accounted for by genetic variants of the responsible P450. However, P450 genetic variants remain largely to be investigated in dogs, a species often used in drug metabolism studies. In this study, the sequencing of 6344 dog genomes found five CYP2C21 variants, including three missense variants (p.K119Q, p.R125C, and p.R329H), one synonymous variant, and one frameshift variant (c.669dupA). The latter creates a premature termination codon that results in the elimination of the heme-binding region and substrate recognition sites 3–6; these are important functional domains, and thus c.669dupA is considered to be a null allele. Some of these variants were found only in a limited number of dogs and breeds, indicating that their distribution may be restricted. Recombinant proteins of the missense variants, co-expressed with NADPH-P450 reductase, were prepared in Escherichia coli for metabolic assays. The CYP2C21 R125C variant showed decreased metabolic capacity compared with the wild-type CYP2C21 protein. These results suggest the possible contribution of genetic variants of CYP2C21 to the variability of drug metabolism in dogs.