Identification of non-functional allelic variant of CYP1A2 in dogs

Abstract

Our results indicate that more than 10% of the dogs studied were CYP1A2-null. Because CYP1A2-null phenotype in dogs affects the results of pharmacokinetic, toxicological and pharmacological studies of drug candidates, these findings are important in the pharmaceutical and the veterinary fields.

Pharmacogenetic and Metabolic Differences Between Dog Breeds: Their Impact on Canine Medicine and the Use of the Dog as a Preclinical Animal Model

“…To date, nine canine CYP isoenzymes have been identified through cloning and sequencing. Five of these isoenzymes have been reported as genetically polymorphic (87)(88)(89)(90). These include CYP1A2, CYP2C41, CYP2D15, CYP2E1 and CYP3A12.…”

Elucidation of the Effects of the CYP1A2 Deficiency Polymorphism in the Metabolism of 4-Cyclohexyl-1-ethyl-7-methylpyrido[2,3-d]pyrimidine-2-(1H)-one (YM-64227), a Phosphodiesterase Type 4 Inhibitor, and Its Metabolites in Dogs

“…In previous studies, a novel CYP1A2 1117 CϾT single nucleotide polymorphism (SNP) was found in beagle dogs, which are used extensively in pharmacology and safety assessment studies (Tenmizu et al, 2004a;Mise et al, 2004a). This SNP resulted in an amino acid change from an Arg codon to a stop codon at position 373, yielding an inactive enzyme.…”

“…In addition, it maintains the ability to inhibit antigen-induced airway responses. For this reason, YM-64227 promises to be a highly effective and safe drug when used as an antiasthmatic or antiinflammatory drug (Iwata et al, 1998).In previous studies, a novel CYP1A2 1117 CϾT single nucleotide polymorphism (SNP) was found in beagle dogs, which are used extensively in pharmacology and safety assessment studies (Tenmizu et al, 2004a;Mise et al, 2004a). This SNP resulted in an amino acid change from an Arg codon to a stop codon at position 373, yielding an inactive enzyme.…”

Phenacetin Pharmacokinetics in CYP1A2-Deficient Beagle Dogs

“…P450 enzymes have been extensively studied in humans and rodents; however, dogs are commonly used for pharmacological and absorption, distribution, metabolism, and excretion/toxicology studies of new drug candidates, and studies of their P450 enzymes and polymorphisms are few (Tenmizu et al, 2006;Zhou et al, 2010). Although genetic polymorphisms have been reported in the dog, our understanding of their contribution to the interindividual variability in drug pharmacokinetics related to pharmaceutical drug development and veterinary practice is limited (Mise et al, 2004a).…”

“…P450 enzymes have been extensively studied in humans and rodents; however, dogs are commonly used for pharmacological and absorption, distribution, metabolism, and excretion/toxicology studies of new drug candidates, and studies of their P450 enzymes and polymorphisms are few (Tenmizu et al, 2006;Zhou et al, 2010). Although genetic polymorphisms have been reported in the dog, our understanding of their contribution to the interindividual variability in drug pharmacokinetics related to pharmaceutical drug development and veterinary practice is limited (Mise et al, 2004a).The CYP1A2 enzyme is expressed in all mammals with few species differences in function or regulation, and all have very similar amino acid sequences (Parkinson and Ogilvie, 2008). In humans, CYP1A2 polymorphisms in the coding region are rare and only occasionally appear to decrease enzyme activity (Faber et al, 2005).…”