Skip to main content
SpringerLink
Log in

Genetic polymorphism of cytochrome P450s in beagles: possible influence of CYP1A2 deficiency on toxicological evaluations

  • Toxicokinetics and Metabolism
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

Abstract

A number of human cytochrome P450 (CYP) isozymes have been shown to be genetically polymorphic, and extensive pharmaceutical studies have been conducted to characterize the clinical relevance of the polymorphism. Although the beagle is extensively used in the safety assessment studies of new drug candidates and agricultural chemicals, only a limited number of studies have been reported on the significance of the CYP isozyme polymorphism in dogs. Recently, a single nucleotide polymorphism that results in a deficiency of canine CYP1A2 was discovered. This deficiency was shown to significantly alter the pharmacokinetic behavior of two drugs, and can be associated with a large inter-individual difference in the kinetic behavior of a third. In this article, the five genetically polymorphic canine CYP isozymes that have been reported so far are reviewed, and the altered pharmacokinetics of the drugs concerned are described. Although little information on toxicological relevance has been reported, it is possible that the modified pharmacokinetics may also cause altered toxic responses as well. This phenomenon may occur only with the types of chemicals that are eliminated mainly through polymorphic-enzyme mediated metabolism. However, it is recommended that genetically pure beagles are used for the toxicity studies and safety assessment of new chemical entities in order to reduce the potential inter-individual differences.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Azuma R, Komuro M, Kawaguchi Y, Okudaira K, Hayashi M, Kiwada H (2002) Comparative analysis of in vitro and in vivo pharmacokinetic parameters related to individual variability of GTS-21 in canine. Drug Metab Pharmacokinet 17:75–82

    Article  PubMed  CAS  Google Scholar 

  • Baldrick P (2003) Toxicokinetics in preclinical evaluation. Drug Discov Today 8:127–133

    Article  PubMed  CAS  Google Scholar 

  • Blaisdell J, Goldstein JA, Bai SA (1998) Isolation of a new canine cytochrome P450 cDNA from the cytochrome P450 2C subfamily (CYP2C41) and evidence for polymorphic differences in its expression. Drug Metab Dispos 26:278–283

    PubMed  CAS  Google Scholar 

  • Ciaccio PJ, Halpert JR (1989) Characterization of a phenobarbital-inducible dog liver cytochrome P450 structurally related to rat and human enzymes of the P450IIIA (steroid-inducible) gene subfamily. Arch Biochem Biophys 271:284–299

    Article  PubMed  CAS  Google Scholar 

  • Ciaccio PJ, Graves PE, Bourque DP, Glinsmann-Gibson B, Halpert JR (1991) cDNA and deduced amino acid sequences of a dog liver cytochrome P-450 of the IIIA gene subfamily. Biochim Biophys Acta 1088:319–322

    PubMed  CAS  Google Scholar 

  • Danielson PB (2002) The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans. Curr Drug Metab 3:561–597

    Article  PubMed  CAS  Google Scholar 

  • Dorne JL (2004) Impact of inter-individual differences in drug metabolism and pharmacokinetics on safety evaluation. Fundam Clin Pharmacol 18:609–620

    Article  PubMed  CAS  Google Scholar 

  • Eguchi K, Nishibe Y, Baba T, Ohno K (1996) Quantitation of cytochrome P450 enzymes (CYP1A1/2, 2B11, 2C21 and 3A12) in dog liver microsomes by enzyme-linked immunosorbent assay. Xenobiotica 26:755–763

    Article  PubMed  CAS  Google Scholar 

  • Fraser DJ, Feyereisen R, Harlow GR, Halpert JR (1997) Isolation, heterologous expression and functional characterization of a novel cytochrome P450 3A enzyme from a canine liver cDNA library. J Pharmacol Exp Ther 283:1425–1432

    PubMed  CAS  Google Scholar 

  • Furuta T, Ohashi K, Kosuge K, Zhao XJ, Takashima M, Kimura M, Nishimoto M, Hanai H, Kaneko E, Ishizaki T (1999) CYP2C19 genotype status and effect of omeprazole on intragastric pH in humans. Clin Pharmacol Ther 65:552–561,

    Article  PubMed  CAS  Google Scholar 

  • Graham MJ, Bell AR, Crewe HK, Moorcraft CL, Walker L, Whittaker EF, Lennard MS (2003) mRNA and protein expression of dog liver cytochromes P450 in relation to the metabolism of human CYP2C substrates. Xenobiotica 33:225–237

    Article  PubMed  CAS  Google Scholar 

  • Graves PE, Elhag GA, Ciaccio PJ, Bourque DP, Halpert JR (1990) cDNA and deduced amino acid sequences of a dog hepatic cytochrome P450IIB responsible for the metabolism of 2,2′,4,4′,5,5′-hexachlorobiphenyl. Arch Biochem Biophys 281:106–115

    Article  PubMed  CAS  Google Scholar 

  • Ingelman-Sundberg M, Oscarson M, McLellan RA (1999) Polymorphic human cytochrome P450 enzymes: an opportunity for individualized drug treatment. Trends Pharmacol Sci 20:342–349

    Article  PubMed  CAS  Google Scholar 

  • Kagimoto M, Heim M, Kagimoto K, Zeugin T, Meyer UA (1990) Multiple mutations of the human cytochrome P450IID6 gene (CYP2D6) in poor metabolizers of debrisoquine. Study of the functional significance of individual mutations by expression of chimeric genes. J Biol Chem 265:17209–17214

    PubMed  CAS  Google Scholar 

  • Lankford SM, Bai SA, Goldstein JA (2000) Cloning of canine cytochrome P450 2E1 cDNA: identification and characterization of two variant alleles. Drug Metab Dispos 28:981–986

    PubMed  CAS  Google Scholar 

  • Lindblad-Toh K, Wade CM, Mikkelsen TS, Karlsson EK, Jaffe DB, Kamal M, Clamp M, Chang JL, Kulbokas EJ 3rd, Zody MC, Mauceli E, Xie X, Breen M, Wayne RK et al (2005) Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature 438:803–819

    Article  PubMed  CAS  Google Scholar 

  • Mealey KL, Bentjen SA, Gay JM, Cantor GH (2001) Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. Pharmacogenetics 11:727–733

    Article  PubMed  CAS  Google Scholar 

  • Meyer UA, Gut J, Kronbach T, Skoda C, Meier UT, Catin T, Dayer P (1986) The molecular mechanisms of two common polymorphisms of drug oxidation–evidence for functional changes in cytochrome P-450 isozymes catalysing bufuralol and mephenytoin oxidation. Xenobiotica 16:449–464

    Article  PubMed  CAS  Google Scholar 

  • Mise M, Hashizume T, Matsumoto S, Terauchi Y, Fujii T (2004a) Identification of non-functional allelic variant of CYP1A2 in dogs. Pharmacogenetics 14:769–773

    Article  CAS  Google Scholar 

  • Mise M, Yadera S, Matsuda M, Hashizume H, Matsumoto S, Terauchi Y, Fujii T (2004b) Polymorphic expression of CYP1A2 leading to interindividual variability in metabolism of a novel benzodiazepine receptor partial inverse agonist in dogs. Drug Metab Dispos 32:240–245

    Article  CAS  Google Scholar 

  • Nakamura A, Yamamoto Y, Tasaki T, Sugimoto C, Masuda M, Kazusaka A, Fujita S (1995) Purification and characterization of a dog cytochrome P450 isozyme belonging to the CYP2D subfamily and development of its antipeptide antibody. Drug Metab Dispos 23:1268–1273

    PubMed  CAS  Google Scholar 

  • Nebert DW, Russell DW (2002) Clinical importance of the cytochromes P450. Lancet 360:1155–1162

    Article  PubMed  CAS  Google Scholar 

  • Nelson DR (1999) Cytochrome P450 and the individuality of species. Arch Biochem Biophys 369:1–10

    Article  PubMed  CAS  Google Scholar 

  • Nishibe Y, Wakabayashi M, Harauchi T, Ohno K, (1998) Characterization of cytochrome P450 (CYP3A12) induction by rifampicin in dog liver. Xenobiotica 28:549–557

    Article  PubMed  CAS  Google Scholar 

  • Nunoya KI, Yokoi T, Kimura K, Kainuma T, Satoh K, Kinoshita M, Kamataki T (1999) A new CYP2A6 gene deletion responsible for the in vivo polymorphic metabolism of (+)-cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one hydrochloride in humans. J Pharmacol Exp Ther 289:437–442

    PubMed  CAS  Google Scholar 

  • Ohta K, Motoya M, Komori M, Miura T, Kitada M, Kamataki T (1990) Interspecies homology of cytochrome P-450: purification and toxicological significance of a high spin form cytochrome P-450 (P-450-D2) from liver microsome of polychlorinated biphenyl (PCB)-treated beagle dogs. J Biopharm Sci 1:59–71

    CAS  Google Scholar 

  • Orphanides G, Kimber I (2003) Toxicogenetics: applications and opportunities. Toxicol Sci 75:1–6

    Article  PubMed  CAS  Google Scholar 

  • Paulson SK, Engel L, Reitz B, Bolten S, Burton EG, Maziasz TJ, Yan B, Schoenhard GL (1999) Evidence for polymorphism in the canine metabolism of the cyclooxygenase 2 inhibitor, celecoxib. Drug Metab Dispos 27:1133–1142

    PubMed  CAS  Google Scholar 

  • Roussel F, Duignan DB, Lawton MP, Obach RS, Strick CA, Tweedie DJ (1998) Expression and characterization of canine cytochrome P450 2D15. Arch Biochem Biophys 357:27–36

    Article  PubMed  CAS  Google Scholar 

  • Sakamoto K, Kirita S, Baba T, Nakamura Y, Yamazoe Y, Kato R, Takanaka A, Matsubara T (1995) A new cytochrome P450 form belonging to the CYP2D in dog liver microsomes: purification, cDNA cloning, and enzyme characterization. Arch Biochem Biophys 319:372–382

    Article  PubMed  CAS  Google Scholar 

  • Salavaggione OE, Kidd L, Prondzinski JL, Szumlanski CL, Pankratz VS, Wang L, Trepanier L, Weinshilboum RM (2002) Canine red blood cell thiopurine S-methyltransferase: companion animal pharmacogenetics. Pharmacogenetics 12:713–724

    Article  PubMed  CAS  Google Scholar 

  • Shou M, Norcross R, Sandig G, Lu P, Li Y, Lin Y, Mei Q, Rodrigues AD, Rushmore TH (2003) Substrate specificity and kinetic properties of seven heterologously expressed dog cytochromes p450. Drug Metab Dispos 31:1161–1169

    Article  PubMed  CAS  Google Scholar 

  • Sullivan-Klose TH, Ghanayem BI, Bell DA, Zhang ZY, Kaminsky LS, Shenfield GM, Miners JO, Birkett DJ, Goldstein JA (1996) The role of the CYP2C9-Leu359 allelic variant in the tolbutamide polymorphism. Pharmacogenetics 6:341–349

    Article  PubMed  CAS  Google Scholar 

  • Tang C, Shou M, Rushmore TH, Mei Q, Sandhu P, Woolf EJ, Rose MJ, Gelmann A, Greenberg HE, De Lepeleire I, Van Hecken A, De Schepper PJ, Ebel DL, Schwartz JI, Rodrigues AD (2001) In-vitro metabolism of celecoxib, a cyclooxygenase-2 inhibitor, by allelic variant forms of human liver microsomal cytochrome P450 2C9: correlation with CYP2C9 genotype and in-vivo pharmacokinetics. Pharmacogenetics 11:223–235

    Article  PubMed  CAS  Google Scholar 

  • Tasaki T, Nakamura A, Itoh S, Ohashi K, Yamamoto Y, Masuda M, Iwata H, Kazusaka A, Kamataki T, Fujita S (1998a) Expression and characterization of dog CYP2D15 using baculovirus expression system. J Biochem 123:162–168

    CAS  Google Scholar 

  • Tasaki T, Iwata H, Kazusaka A, Fujita S (1998b) Regio- and stereoselectivity in propranolol metabolism by dog liver microsomes and the expressed dog CYP2D15. J Biochem 123:747–751

    CAS  Google Scholar 

  • Tenmizu D, Endo Y, Noguchi K, Kamimura H (2004) Identification of the novel canine CYP1A2 1117 C > T SNP causing protein deletion. Xenobiotica 34:835–846

    Article  PubMed  CAS  Google Scholar 

  • Tenmizu D, Noguchi K, Kamimura H, Ohtani H, Sawada Y (2006) The canine CYP1A2 deficiency polymorphism dramatically affects the pharmacokinetics of YM-64227, a phosphodiesterase type 4 inhibitor. Drug Metab Dispos 34:800–806

    Article  PubMed  CAS  Google Scholar 

  • Trevillyan JM, Chiou XG, Chen YW, Ballaron SJ, Sheets MP, Smith ML, Wiedeman PE, Warrior U, Wilkins J, Gubbins EJ, Gagne GD, Fagerland J, Carter GW, Luly JR, Mollison KW, Djuric SW (2001) Potent inhibition of NFAT activation and T cell cytokine production by novel low molecular weight pyrazole compounds. J Biol Chem 276:48118–48126

    PubMed  CAS  Google Scholar 

  • Uchida T, Komori M, Kitada M, Kamataki T (1990) Isolation of cDNAs coding for three different forms of liver microsomal cytochrome P-450 from polychlorinated biphenyl-treated beagle dogs. Mol Pharmacol 38:644–651

    PubMed  CAS  Google Scholar 

  • Walton K, Dorne JL, Renwick AG (2001) Uncertainty factors for chemical risk assessment: interspecies differences in the in vivo pharmacokinetics and metabolism of human CYP1A2 substrates. Food Chem Toxicol 39:667–680

    Article  PubMed  CAS  Google Scholar 

  • Zhong WZ, Williams MG, Branstetter DG (2000) Toxicokinetics in drug development: an overview of toxicokinetic application in the development of PNU-101017, an anxiolytic drug candidate. Curr Drug Metab 1:243–254

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Drug Metabolism Research Laboratories, Astellas Pharma Inc., Azusawa 1-1-8, Itabashi-ku, Tokyo, 174-8511, Japan

    H. Kamimura

Authors
  1. H. Kamimura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H. Kamimura.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kamimura, H. Genetic polymorphism of cytochrome P450s in beagles: possible influence of CYP1A2 deficiency on toxicological evaluations. Arch Toxicol 80, 732–738 (2006). https://doi.org/10.1007/s00204-006-0100-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00204-006-0100-6

Keywords

Search

Navigation