Analysis of polymorphisms of canine Cytochrome P 450‐CYP2D15

Abstract

Cytochrome P450 (CYP) proteins constitute a large ancient family of oxidative enzymes essential for the efficient elimination of a wide variety of clinically used drugs. Polymorphic variants of human CYP2D6 are associated with the conversion rate and efficacy of several drugs such as antidepressants. Polymorphisms of the canine orthologue CYP2D15 are of interest because these antidepressants are also used in dogs with behavioral problems and the outcome of the treatment is variable. However, the annotated CYP2D15 gene is incomplete and inaccurately assembled in CanFam3.1, hampering DNA sequence analysis of the gene in individual dogs. We elucidated the complete exon–intron structure of CYP2D15 to enable comprehensive genotyping of the gene using genomic DNA. We surveyed variations of the gene in four diverse dog breeds and identified novel polymorphisms in exon 2 in border collies. Further investigation to establish the impact of these canine CYP2D15 polymorphisms on interindividual variability in expression and function of this metabolizing enzyme is now feasible. Further knowledge of CYP pharmacogenetics will help individualize therapy and thereby increase therapeutic efficacy, especially in the use of antidepressants in veterinary behavioral medicine.

Association of cytochrome P450 2D15 (CYP2D15) nonsynonymous polymorphisms and exon 3 deleted RNA splice variant with CYP2D15 protein content and enzyme function in dog liver microsomes

“…Haplotypes were inferred from genotypes of five nonsynonymous variants determined using DNA from the same livers. Haplotypes are shown in Table 3 Our genotyping results can be compared to a previous study (Van Hagen et al, 2020) that evaluated the same CYP2D15 polymorphisms in border collies, English cocker spaniels, rottweilers, and bull mastiffs. Although the numbers of dogs evaluated from each breed in that study were relatively small (12 each, 48 total), the results indicated that there may be substantial differences in allele prevalence between breeds for some variants.…”

Validation of a Chromosome 14 Risk Haplotype for Idiopathic Epilepsy in the Belgian Shepherd Dog Found to Be Associated with an Insertion in the RAPGEF5 Gene

“…Buccal swabs or whole blood samples were collected by owners or veterinarians, respectively, and submitted to the study. Sample DNA from the US, Finland, and the Netherlands was processed as previously described [ 7 , 8 , 9 ]. The DNA was then genotyped for the CFA14 and 37 risk SNPs using variant-specific PCR primers and a standard PCR protocol ( Table S1 ).…”

Clinical pharmacology of tramadol and tapentadol, and their therapeutic efficacy in different models of acute and chronic pain in dogs and cats

“…CYP2D is solely responsible for M1 production in dogs, and mutant alleles have been linked to differences between species and breeds [ 38 ]. For instance, in Bullmastiffs, Border collies, Rottweilers, and English cocker spaniels, van Hagen et al [ 39 ] reported that all breeds demonstrate differences in coding sequences or exons 4, 5, and 6, but differences in exon 2 were exclusively detected in the Border collies. In other CYPs, such as the CYP2C41 gene, the site of gene deletion was consistently absent in Bearded Collies, Boxers, Bernese Mountains, Briards, French bulldogs, and Irish Wolfhounds.…”

“…Although in vivo and clinical trials to determine the pharmacokinetics of tramadol within breeds are limited, these genetic modifications are associated with poor antinociceptive effects in Beagles, as mentioned by Kögel et al [ 21 ] and Schütter et al [ 41 ]. However, not all polymorphisms result in enzymatic deficits, indicating that the capacity of the mutant CYP is not always reduced [ 39 ]. In the case of dogs, this implies that, based on the available data and inconsistencies between breeds, therapeutic dosing can be less efficacious in some dogs due to high enzymatic biotransformation, increased clearance, and minimal plasma concentrations [ 42 ], or could be attributed to a metabolically less active enzyme that produces fewer active metabolites [ 39 ].…”

“…However, not all polymorphisms result in enzymatic deficits, indicating that the capacity of the mutant CYP is not always reduced [ 39 ]. In the case of dogs, this implies that, based on the available data and inconsistencies between breeds, therapeutic dosing can be less efficacious in some dogs due to high enzymatic biotransformation, increased clearance, and minimal plasma concentrations [ 42 ], or could be attributed to a metabolically less active enzyme that produces fewer active metabolites [ 39 ].…”