J Vet Sci.  2015 Sep;16(3):273-280. 10.4142/jvs.2015.16.3.273.

SNP genetic polymorphisms of MDR-1, CYP1A2 and CYPB11 genes in four canine breeds upon toxicological evaluation

• Gagliardi
• Llambi S
• Arruga MV

• KMID: 2344299
• DOI: http://doi.org/10.4142/jvs.2015.16.3.273

Abstract

The fields of pharmacogenetics and pharmacogenomics have become increasingly promising regarding the clinical application of genetic data to aid in prevention of adverse reactions. Specific screening tests can predict which animals express modified proteins or genetic sequences responsible for adverse effects associated with a drug. Among the genetic variations that have been investigated in dogs, the multidrug resistance gene (MDR) is the best studied. However, other genes such as CYP1A2 and CYP2B11 control the protein syntheses involved in the metabolism of many drugs. In the present study, the MDR-1, CYP1A2 and CYP2B11 genes were examined to identify SNP polymorphisms associated with these genes in the following four canine breeds: Uruguayan Cimarron, Border Collie, Labrador Retriever and German Shepherd. The results revealed that several SNPs of the CYP1A2 and CYP2B11 genes are potential targets for drug sensitivity investigations.

Keyword

dog; drug resistance; pharmacogenomics; SNP polymorphisms

MeSH Terms

Animals
Aryl Hydrocarbon Hydroxylases/*genetics/metabolism
Cytochrome P-450 CYP1A2/*genetics/metabolism
Dogs/*genetics/metabolism
P-Glycoprotein/*genetics/metabolism
*Polymorphism, Single Nucleotide
Steroid Hydroxylases/*genetics/metabolism
Aryl Hydrocarbon Hydroxylases
Cytochrome P-450 CYP1A2
P-Glycoprotein
Steroid Hydroxylases

Figure

• 

  Fig. 1 Locations of the three studied genes.

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  Fig. 2 Genetic distances between the four studied breeds.

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  Fig. 3 Genetic distances for animals and breeds when all animals are represented.

Reference

1. Altschul SF, Madden TL, Schäffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 1997; 25:3389–3402.

2. Alves L, Hülsmeyer V, Jaggy A, Fischer A, Leeb T, Drögemüller M. Polymorphisms in the ABCB1 gene in phenobarbital responsive and resistant idiopathic epileptic Border Collies. J Vet Intern Med. 2011; 25:484–489.

3. Aretz JS, Geyer J. Detection of the CYP1A2 1117C > T polymorphism in 14 dog breeds. J Vet Pharmacol Ther. 2011; 34:98–100.

4. Baratta MT, Zaya MJ, White JA, Locuson CW. Canine CYP2B11 metabolizes and is inhibited by anesthetic agents often co-administered in dogs. J Vet Pharmacol Ther. 2009; 33:50–55.

5. Belkhir K, Borsa P, Chikhi L, Raufaste N, Bonhomme F. GENETIX 4.05, Windows TM soft for population genetics. Laboratoire Génome, Populations, Interactions, Université de Montpellier II, Montpellier: 1996-2004.

6. Excoffier L, Laval G, Schneider S. Arlequin (version 3.0): an integrated software package for population genetics data analysis. Evol Bioinform Online. 2005; 1:47–50.

7. Fontana RJ, Lown KS, Paine MF, Fortlage L, Santella RM, Felton JS, Knize MG, Greenberg A, Watkins PB. Effects of a chargrilled meat diet on expression of CYP3A, CYP1A, and P-glycoprotein levels in healthy volunteers. Gastroenterology. 1999; 117:89–98.

8. Gagliardi R, García C, Llambí S, Arruga M. Analysis of mdr1-1Δ mutation of MDR-1 gene in the "Cimarron Uruguayo" dog. Rev MVZ Córdoba. 2013; 18:3480–3483.

9. Gagliardi R, Llambí S, García C, Arruga M. Preliminary studies of the genetic structure of "Cimarron uruguayo" dog using microsatellite markers. Rev MVZ Córdoba. 2010; 15:2234–2239.

10. Gagliardi R, Llambí S, García CB, Arruga MV. Microsatellite characterization of Cimarron Uruguayo dogs. Genet Mol Biol. 2011; 34:165–168.

11. Gagliardi R, Llambí S, Arruga MV. Molecular study of gene CYP2D15 (Cytochrome P450 2D15) in Cimarron Uruguayo dog. Acta Iberoam Conserv Anim. 2011; 1:313–315.

12. Graham RA, Downey A, Mudra D, Krueger L, Carroll K, Chengelis C, Madan A, Parkinson A. In vivo and in vitro induction of cytochrome P450 enzymes in beagle dogs. Drug Metab Dispos. 2002; 30:1206–1213.

13. Hall TA. BioEdit: a user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT. Nucleic Acids Symp Ser. 1999; 41:95–98.

14. Kamimura H. Genetic polymorphism of cytochrome P450s in beagles: possible influence of CYP1A2 deficiency on toxicological evaluations. Arch Toxicol. 2006; 80:732–738.

15. Karriker M. Genetic predisposition to adverse reactions drug in dogs. Vet Focus (Boulogne). 2007; 17:11–17.

16. Lankas GR, Cartwright ME, Umbenhaur D. P-glycoprotein deficiency in subpopulation of CF-1 mice enhances avermectin-induced neurotoxicity. Toxicol Appl Pharmacol. 1997; 143:357–365.

17. Lebart L, Morineau A, Warwick KM. Multivariate Descriptive Statistical Analysis: Correspondence Analysis and Related Techniques for Large Matrices (Probability & Mathematical Statistics). John Wiley & Sons, Chichester;1984.

18. 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, Ostrander EA, Ponting CP, Galibert F, Smith DR, DeJong PJ, Kirkness E, Alvarez P, Biagi T, Brockman W, Butler J, Chin CW, Cook A, Cuff J, Daly MJ, DeCaprio D, Gnerre S, Grabherr M, Kellis M, Kleber M, Bardeleben C, Goodstadt L, Heger A, Hitte C, Kim L, Koepfli KP, Parker HG, Pollinger JP, Searle SM, Sutter NB, Thomas R, Webber C, Baldwin J, Abebe A, Abouelleil A, Aftuck L, Ait-Zahra M, Aldredge T, Allen N, An P, Anderson S, Antoine C, Arachchi H, Aslam A, Ayotte L, Bachantsang P, Barry A, Bayul T, Benamara M, Berlin A, Bessette D, Blitshteyn B, Bloom T, Blye J, Boguslavskiy L, Bonnet C, Boukhgalter B, Brown A, Cahill P, Calixte N, Camarata J, Cheshatsang Y, Chu J, Citroen M, Collymore A, Cooke P, Dawoe T, Daza R, Decktor K, DeGray S, Dhargay N, Dooley K, Dooley K, Dorje P, Dorjee K, Dorris L, Duffey N, Dupes A, Egbiremolen O, Elong R, Falk J, Farina A, Faro S, Ferguson D, Ferreira P, Fisher S, FitzGerald M, Foley K, Foley C, Franke A, Friedrich D, Gage D, Garber M, Gearin G, Giannoukos G, Goode T, Goyette A, Graham J, Grandbois E, Gyaltsen K, Hafez N, Hagopian D, Hagos B, Hall J, Healy C, Hegarty R, Honan T, Horn A, Houde N, Hughes L, Hunnicutt L, Husby M, Jester B, Jones C, Kamat A, Kanga B, Kells C, Khazanovich D, Kieu AC, Kisner P, Kumar M, Lance K, Landers T, Lara M, Lee W, Leger JP, Lennon N, Leuper L, LeVine S, Liu J, Liu X, Lokyitsang Y, Lokyitsang T, Lui A, Macdonald J, Major J, Marabella R, Maru K, Matthews C, McDonough S, Mehta T, Meldrim J, Melnikov A, Meneus L, Mihalev A, Mihova T, Miller K, Mittelman R, Mlenga V, Mulrain L, Munson G, Navidi A, Naylor J, Nguyen T, Nguyen N, Nguyen C, Nguyen T, Nicol R, Norbu N, Norbu C, Novod N, Nyima T, Olandt P, O'Neill B, O'Neill K, Osman S, Oyono L, Patti C, Perrin D, Phunkhang P, Pierre F, Priest M, Rachupka A, Raghuraman S, Rameau R, Ray V, Raymond C, Rege F, Rise C, Rogers J, Rogov P, Sahalie J, Settipalli S, Sharpe T, Shea T, Sheehan M, Sherpa N, Shi J, Shih D, Sloan J, Smith C, Sparrow T, Stalker J, Stange-Thomann N, Stavropoulos S, Stone C, Stone S, Sykes S, Tchuinga P, Tenzing P, Tesfaye S, Thoulutsang D, Thoulutsang Y, Topham K, Topping I, Tsamla T, Vassiliev H, Venkataraman V, Vo A, Wangchuk T, Wangdi T, Weiand M, Wilkinson J, Wilson A, Yadav S, Yang S, Yang X, Young G, Yu Q, Zainoun J, Zembek L, Zimmer A, Lander ES. Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature. 2005; 438:803–819.

19. Mancinelli L, Cronin M, Sadée W. Pharmacogenomics: the promise of personalized medicine. AAPS PharmSci. 2000; 2:324–329.

20. McWilliam H, Li W, Uludag M, Squizzato S, Park YM, Buso N, Cowley AP, Lopez R. Analysis tool web services from the EMBL-EBI. Nucleic Acids Res. 2013; 41(W1):W597–W600.

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

22. Mizukami K, Yabuki A, Chang HS, Uddin MM, Rahman MM, Kushida K, Kohyama M, Yamato O. High frequency of a single nucleotide substitution (c.-6-180T>G) of the canine MDR1/ABCB1 gene associated with phenobarbital-resistant idiopathic epilepsy in Border Collie dogs. Dis Markers. 2013; 35:669–672.

23. Muñana KR, Nettifee-Osborne JA, Bergman RL Jr, Mealey KL. Association between ABCB1 genotype and seizure outcome in Collies with epilepsy. J Vet Intern Med. 2012; 26:1358–1364.

24. Neff MW, Robertson KR, Wong AK, Safra N, Broman KW, Slatkin M, Mealey KL, Pedersen NC. Breed distribution and history of canine mdr1-1Δ, a pharmacogenetic mutation that marks the emergence of breeds from the collie lineage. Proc Natl Acad Sci U S A. 2004; 101:11725–11730.

25. Solé X, Guinó E, Valls J, Iniesta R, Moreno V. SNPStats: a web tool for the analysis of association studies. Bioinformatics. 2006; 22:1928–1929.

26. Talakad JC, Wilderman PR, Davydov DR, Kumar S, Halpert JR. Rational engineering of cytochromes P450 2B6 and 2B11 for enhanced stability: insights into structural importance of residue 334. Arch Biochem Biophys. 2010; 494:151–158.

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

28. Tomiyasu H, Goto-Koshino Y, Fujino Y, Ohno K, Tsujimoto H. Epigenetic regulation of the ABCB1 gene in drugsensitive and drug-resistant lymphoid tumour cell lines obtained from canine patients. Vet J. 2014; 199:103–109.

29. Walsky RL, Astuccio AV, Obach RS. Evaluation of 227 drugs for in vitro inhibition of cytochrome P450 2B6. J Clin Pharmacol. 2006; 46:1426–1438.

30. Whiterock VJ, Delmonte TA, Hui LE, Orcutt TL, Sinz MW. Frequency of CYP1A2 polymorphism in beagle dogs. Drug Metab Lett. 2007; 1:163–165.

31. Whiterock VJ, Morgan DG, Lentz KA, Orcutt TL, Sinz MW. Phenacetin pharmacokinetics in CYP1A2-deficient beagle dogs. Drug Metab Dispos. 2012; 40:228–231.