Identification of non-functional allelic variant of CYP1A2 in dogs

Pharmacogenetics. 2004 Nov;14(11):769-73. doi: 10.1097/00008571-200411000-00008.


Objectives: Recently, we reported that AC-3933, a novel cognitive enhancer, is polymorphically hydroxylated in beagle dogs and that dogs could be phenotyped as extensive metabolizers (EM) or poor metabolizers (PM). AC-3933 polymorphic hydroxylation is caused by polymorphic expression of CYP1A2 protein in dog liver.

Methods: In order to clarify the mechanism of polymorphic expression of CYP1A2 protein in beagle dogs, we investigated, in this study, the sequence of CYP1A2 cDNA in EM and PM dogs.

Results: In PM dogs CYP1A2 gene, we discovered a nonsense mutation (C1117T) that induces a premature termination, and is associated with PM phenotype for AC-3933 hydroxylation. All PM dogs studied were homozygote of the mutant allele (m/m) and seemed to be CYP1A2-null phenotype as they lacked the heme-binding region in CYP1A2. These results indicate that the polymorphic expression of CYP1A2 protein observed in our previous study is caused by a single nucleotide polymorphism on CYP1A2 coding region. Furthermore, we developed a genotyping method for the mutant allele using a mismatch PCR-restriction fragment length polymorphism, and carried out frequency analysis in 149 beagle dogs.

Conclusion: 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.

MeSH terms

  • Alleles*
  • Animals
  • Base Sequence
  • Cytochrome P-450 CYP1A2 / genetics*
  • Cytochrome P-450 CYP1A2 / metabolism
  • DNA Primers
  • DNA, Complementary
  • Dogs
  • Genotype
  • Liver / enzymology
  • Phenotype
  • Polymorphism, Single Nucleotide


  • DNA Primers
  • DNA, Complementary
  • Cytochrome P-450 CYP1A2