Investigation of Ivermectin Susceptibility in Kangal and Akbaş Dogs via MDR1 Gene Mutation
Year 2024,
Volume: 13 Issue: 1, 1 - 7, 25.06.2024
Emine Baydan
,
Bengi Cınar Kul
,
Mustafa Yenal Akkurt
,
Ebru Yıldırım
,
Emre Arslanbaş
,
Farah Gönül Aydın
Abstract
This research aimed to investigate the sensitivity to the drug (ivermectin) in Kangal and Akbaş breed dogs, which are dog breeds native to Turkey, via the MDR1 gene mutation.
For the research, blood, hair and intraoral swap samples were taken from 30 Kangal and 20 Akbaş breed dogs (male-female mixed, adult) with ethical permission and approval forms. Kangal dog samples were taken from the dogs bred in the farms in Sivas center and Kangal village, and Akbaş dog samples were taken from the dogs bred in the farms in the Sivrihisar center, Ankara and Eskişehir regions. The samples taken were evaluated based on polymerase chain reaction (PCR) from the wool and subsequent two-way dideoxy chain termination reaction in the presence of 4 base farm deletions (c.296-299delAGAT) in the 4th exon of the ABCB1 gene that encodes the P-glycoprotein (P-gp) drug transporter protein.
According to the obtained DNA sequence results, the deletion of “AGAT” was not determined in any of the individuals screened. The results of this study, which is preliminary research, showed that Kangal and Akbaş breed dogs are safe in terms of sensitivity to drugs that are set to be absorbed and excreted by the P-gp pump, especially ivermectin. However, it would be useful to repeat the analysis of both breeds with more examples.
Ethical Statement
This study was approved by the Ankara University Animal Experiments Local Ethics Committee (10.02.2016, 2016-3-21 Number Ethics Committee Decision). In addition, the authors declared that Research and Publication Ethical rules were followed.
Supporting Institution
This work has been supported by Ankara University Scientific Research Projects Coordination Unit under grant number 17B0239002.
Project Number
Ankara University Scientific Research Projects Coordination Unit, grant number 17B0239002.
Thanks
This work has been supported by Ankara University Scientific Research Projects Coordination Unit under grant number 17B0239002.
References
- Altunok V, Koban E, Chikhi L, Schaffer A, Pedersen NC, Nizamlioglu M, Togan I, 2005: Genetic evidence for the distinctness of Kangal dogs. Bull Vet Inst Pulawy, 49(2), 249-254.
- Asawakarn S, Ruangchaiprakarn V, Srisowanna N, Wongwan L, Kanuengthong A, Suriyaphol G, 2012: Determination of multidrug resistance (MDR1) gene and its mutations in dogs by using polymerase chain reaction. Thai J Vet Med, 42(1), 37-42.
- Atasoy F, Uğurlu M, Özarslan B, Yakan A, 2011: Halk elinde yetiştirilen Akbaş köpeklerinde canlı ağırlık ve vücut ölçüleri. Ankara Üniv Vet Fak Derg, 58, 213-215.
- Atasoy F, Ünal N, Kanlı O, Yakan A, 2005: Damızlık Kangal köpeklerinde canlı ağırlık ve bazı vücut ölçüleri. Lalahan Hay Araşt Enst Derg, 45(1), 33-39.
- Beckers E, Casselman I, Soudant E, Daminet S, Paepe D, Peelman L, Broeckx BJ, 2022: The prevalence of the ABCB1-1Δ variant in a clinical veterinary setting: The risk of not genotyping. Plos one, 17(8), e0273706.
- Barroso MC, Grilo A, Aguiar S, Aires da Silva F, São Braz B, 2022: Occurrence of MDR1 1-delta mutation in herding dog breeds in Portugal. Front Vet Sci, 9, 990884.
- Çoban Ö, Yildiz A, Sabuncuoğlu N, Laçin E, Yildirim F, 2011: Kangal Köpeği yavrularında vücut ağırlığı değişimlerinin tanımlanmasında doğrusal olmayan büyüme modellerinin kullanılması. Atatürk Üniv Vet Bil Derg, 6(1), 17-22.
- Dekel Y, Machluf Y, Stoler A, Aderet A, Baumel D, Kellerman E, Plotsky Y, Noked Partouche O, Elhalal G, Ben-Shlomo I, 2017: Frequency of canine nt230 (del4) MDR1 mutation in prone pure breeds, their crosses and mongrels in Israel-insights from a worldwide comparative perspective. BMC vet res, 13(1), 1-8.
- Elewa H, Awaisu A, 2019: Pharmacogenomics in pharmacy practice: Current perspectives. Integr Pharm Res Pract, 8, 97-104.
- Erkens T, Daminet S, Rogiers C, Gommeren K, Lampo E, Vander Donckt D, Van den Broeke A, Van Poucke M, Van Zeveren A, Peelman LJ, 2009: Presence of the ABCB1 (MDR1) deletion mutation causing ivermectin hypersensitivity in certain dog breeds in Belgium. Vlaams Diergeneeskundig Tijdschrift, 78(4), 256-260.
- Erol B, 2008: Kangal köpeklerinde bazı faktörlerin dölverimi, yaşama gücü ve büyüme üzerine etkisi. Doctoral dissertation, University of Ankara.
- Gagliardi R, García GC, Llambí DS, Arruga LM, 2013: Analysis of mdr1-1Δ mutation of MDR1 gene in the "Cimarron Uruguayo" dog. Rev MVZ Córdoba, 18(2), 3480-3483.
- Gagliardi R, Martínez AD, Tellechea HB, Sitjar QP, Llambí DS, Arruga LM, 2015: The search for the mdr1-1Δ mutation of the MDR1 gene in four canine breeds in Uruguay (preliminary study). Rev MVZ Córdoba, 20(1), 4482-4487.
- Geyer J, Döring B, Godoy JR, Leidolf R, Moritz A, Petzinger E, 2005: Frequency of the nt230 (del4) MDR1 mutation in Collies and related dog breeds in Germany. J Vet Pharmacol Therap, 28(6), 545-551.
- Geyer J, Janko C, 2012: Treatment of MDR1 mutant dogs with macrocyclic lactones. Curr pharm biotechnol, 13(6), 969-986.
- Gramer I, Leidolf R, Döring B, Klintzsch S, Krämer EM, Yalcin E, Petzinger E, Geyer J, 2011: Breed distribution of the nt230 (del4) MDR1 mutation in dogs. Vet J, 189(1), 67-71.
- Hall TA (1999). BioEdit: a user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT. In: Nucleic acids symposium series. (Vol. 41, No. 41), 95-98, Information Retrieval Ltd., London.
Hürlimann E, Hofmann D, Keiser J, 2023: Ivermectin and moxidectin against soil-transmitted helminth infections. Trends Parasitol, 39(4), 272-284.
- Janko C, Geyer J, 2013: Moxidectin has a lower neurotoxic potential but comparable brain penetration in P‐glycoprotein‐deficient CF‐1 mice compared to ivermectin. J Vet Pharmacol Ther, 36(3), 275-284.
Kawabata A, Momoi Y, Inoue-Murayama M, Iwasaki T, 2005: Canine mdr1 gene mutation in Japan. J vet med sci, 67(11), 1103-1107.
- Koban E, Saraç ÇG, Açan SC, Savolainen P, Togan İ, 2009: Genetic relationship between Kangal, Akbash and other dog populations. Discrete Appl Math, 157(10), 2335-2340.
- Koressaar T, Remm M, 2007: Enhancements and modifications of primer design program Primer3. Bioinformatics, 23(10), 1289-1291.
- Lerdkrai C, Phungphosop N, 2021: Prevalence of the MDR1 gene mutation in herding dog breeds and Thai Ridgebacks in Thailand. Vet World, 14(11), 3015-3020.
- Linardi RL, Natalini CC, 2006: Multi-drug resistance (MDR1) gene and P-glycoprotein influence on pharmacokinetic and pharmacodymanic of therapeutic drugs. Ciênc Rural, 36, 336-341.
- Löscher W, 2023: Is the antiparasitic drug ivermectin a suitable candidate for the treatment of epilepsy?. Epilepsia, 64(3), 553-566.
- Marelli SP, Polli M, Frattini S, Cortellari M, Rizzi R, Crepaldi P, 2020: Genotypic and allelic frequencies of MDR1 gene in dogs in Italy. Vet Rec Open, 7(1), e000375.
- Martinez M, Modric S, Sharkey M, Troutman L, Walker L, Mealey K, 2008: The pharmacogenomics of P‐glycoprotein and its role in veterinary medicine. J Vet Pharmacol Therap, 31(4), 285-300.
- 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, 727-33.
- Mealey KL, Meurs KM, 2008: Breed distribution of the ABCB1-1Δ (multidrug sensitivity) polymorphism among dogs undergoing ABCB1 genotyping. J Am Vet Med Assoc, 233(6), 921-924.
- Mealey KL, Owens JG, Freeman E, 2023: Canine and feline P‐glycoprotein deficiency: What we know and where we need to go. J Vet Pharmacol Therap, 46(1), 1-16.
- Ministry of Agriculture and Rural Affairs, 2009: Türkiye Evcil Hayvan Genetik Kaynakları Tanıtım Kataloğu. Birinci Basım. http://www.tarim.gov.tr/TAGEM/Belgeler/yayin/Katalog%20T%C3%BCrk%C3%A7e.pdf
- Monobe MM, Junior JPA, Lunsford KV, Silva RC, Bulla C, 2015: Frequency of the MDR1 mutant allele associated with multidrug sensitivity in dogs from Brazil. Vet Med (Auckl), 6, 111-117.
- Monobe MM, Lunsford KV, Araújo Júnior JP, Bulla C, 2013: Detection of heterozygous MDR1 nt230 (del4) mutation in a mixed-breed dog: case report of possible doxorubicin toxicosis. Vet Med, 4, 35-38.
- Tappin S, Goodfellow M, Peters I, Day M, Hall E, Mealey K, 2012: Frequency of the mutant MDR1 allele in dogs in the UK. Vet Rec, 171(72), 10.1136.
- Tepeli C, Çetin O, İnal Ş, Kırıkçı K, Yılmaz A, 2003: Kangal ve Akbaş Irkı Türk Çoban Köpeklerinde Büyüme Özellikleri. Turk J Vet Anim Sci, 27(4), 1011-1018.
- Turner T, 2005: Priscribing for dogs, Priscribing for cats In: The Veterinary Formulary, Bishop Y (Ed), (Sixth Edt.), 43-45, Pharmaceutical Press, London.
- Upadhyay S, Shrivastava S, Kumar D, Kabra A, Baghel US, 2019: Pharmacoepidemiology: A review. AJPRD, 7(2), 83-87.
- Yıldırım A, 2012: Kangal Irkı Köpeklerde Büyüme ve Beden Ölçülerine ait Özellikler. J Inst Sci Tech, 2(3), 117-126.
Yilmaz O, Aktan S, Ertugrul M, 2012: Türkiye yerli ve yeni köpek ırkları. In: International Animal Science Congress of Turkish and Relatives Communities. pp: 39-52.
- Yilmaz O, Sireli HD, Ertugrul M, 2015: The shepherd dog breeds in Turkey: a survey. ROAVS, 5(4), 172-177.
Kangal ve Akbaş Irkı Köpeklerde MDR1 Gen Mutasyonu Üzerinden İvermektine Duyarlılığın Araştırılması
Year 2024,
Volume: 13 Issue: 1, 1 - 7, 25.06.2024
Emine Baydan
,
Bengi Cınar Kul
,
Mustafa Yenal Akkurt
,
Ebru Yıldırım
,
Emre Arslanbaş
,
Farah Gönül Aydın
Abstract
Bu araştırmada, Türkiye’ye özgü iki farklı ırk köpekte (Kangal ve Akbaş) ivermektine duyarlılığın gen mutasyonu (MDR1) üzerinden belirlenmesi amaçlanmıştır.
Araştırma için, etik izni ve onam formu bulunan 30 adet Kangal ve 20 adet Akbaş ırkı köpekten (erkek dişi karışık, erişkin) kan, kıl ve ağız içi svap örneği alınmıştır. Kangal köpek örnekleri Sivas merkez ve Kangal köyünde yetiştirilen çiftliklerdeki köpeklerden, Akbaş köpek örnekleri ise, Sivrihisar merkez, Ankara ve Eskişehir bölgesindeki çiftliklerde yetiştirilen köpeklerden alınmıştır. Alınan örnekler P-glycoprotein (P-gp) drug transporter proteinini kodlayan ABCB1 (MDR1) geninin 4. ekzonunda 4 baz çiftlik delesyonun (c.296-299delAGAT) varlığı yününden Polimeraz Zincir Reaksiyonu (PZR) ve takiben çift yönlü dideoksi zincir sonlanma reaksiyonuna göre değerlendirilmiştir.
Elde edilen DNA dizi sonuçlarına göre “AGAT” delesyonu taranan hiçbir köpekte belirlenmemiştir. Bir ön araştırma niteliğinde olan bu çalışmanın sonuçları, Kangal ve Akbaş ırkı köpeklerin başta ivermektin olmak üzere P-gp pompası ile emilme ve atılmaları ayarlanan ilaçlara karşı duyarlılık yönünden güvende olduklarını göstermiştir. Ancak, her iki ırka ait analizlerin daha çok örnekle tekrarlanması yararlı olacaktır.
Project Number
Ankara University Scientific Research Projects Coordination Unit, grant number 17B0239002.
References
- Altunok V, Koban E, Chikhi L, Schaffer A, Pedersen NC, Nizamlioglu M, Togan I, 2005: Genetic evidence for the distinctness of Kangal dogs. Bull Vet Inst Pulawy, 49(2), 249-254.
- Asawakarn S, Ruangchaiprakarn V, Srisowanna N, Wongwan L, Kanuengthong A, Suriyaphol G, 2012: Determination of multidrug resistance (MDR1) gene and its mutations in dogs by using polymerase chain reaction. Thai J Vet Med, 42(1), 37-42.
- Atasoy F, Uğurlu M, Özarslan B, Yakan A, 2011: Halk elinde yetiştirilen Akbaş köpeklerinde canlı ağırlık ve vücut ölçüleri. Ankara Üniv Vet Fak Derg, 58, 213-215.
- Atasoy F, Ünal N, Kanlı O, Yakan A, 2005: Damızlık Kangal köpeklerinde canlı ağırlık ve bazı vücut ölçüleri. Lalahan Hay Araşt Enst Derg, 45(1), 33-39.
- Beckers E, Casselman I, Soudant E, Daminet S, Paepe D, Peelman L, Broeckx BJ, 2022: The prevalence of the ABCB1-1Δ variant in a clinical veterinary setting: The risk of not genotyping. Plos one, 17(8), e0273706.
- Barroso MC, Grilo A, Aguiar S, Aires da Silva F, São Braz B, 2022: Occurrence of MDR1 1-delta mutation in herding dog breeds in Portugal. Front Vet Sci, 9, 990884.
- Çoban Ö, Yildiz A, Sabuncuoğlu N, Laçin E, Yildirim F, 2011: Kangal Köpeği yavrularında vücut ağırlığı değişimlerinin tanımlanmasında doğrusal olmayan büyüme modellerinin kullanılması. Atatürk Üniv Vet Bil Derg, 6(1), 17-22.
- Dekel Y, Machluf Y, Stoler A, Aderet A, Baumel D, Kellerman E, Plotsky Y, Noked Partouche O, Elhalal G, Ben-Shlomo I, 2017: Frequency of canine nt230 (del4) MDR1 mutation in prone pure breeds, their crosses and mongrels in Israel-insights from a worldwide comparative perspective. BMC vet res, 13(1), 1-8.
- Elewa H, Awaisu A, 2019: Pharmacogenomics in pharmacy practice: Current perspectives. Integr Pharm Res Pract, 8, 97-104.
- Erkens T, Daminet S, Rogiers C, Gommeren K, Lampo E, Vander Donckt D, Van den Broeke A, Van Poucke M, Van Zeveren A, Peelman LJ, 2009: Presence of the ABCB1 (MDR1) deletion mutation causing ivermectin hypersensitivity in certain dog breeds in Belgium. Vlaams Diergeneeskundig Tijdschrift, 78(4), 256-260.
- Erol B, 2008: Kangal köpeklerinde bazı faktörlerin dölverimi, yaşama gücü ve büyüme üzerine etkisi. Doctoral dissertation, University of Ankara.
- Gagliardi R, García GC, Llambí DS, Arruga LM, 2013: Analysis of mdr1-1Δ mutation of MDR1 gene in the "Cimarron Uruguayo" dog. Rev MVZ Córdoba, 18(2), 3480-3483.
- Gagliardi R, Martínez AD, Tellechea HB, Sitjar QP, Llambí DS, Arruga LM, 2015: The search for the mdr1-1Δ mutation of the MDR1 gene in four canine breeds in Uruguay (preliminary study). Rev MVZ Córdoba, 20(1), 4482-4487.
- Geyer J, Döring B, Godoy JR, Leidolf R, Moritz A, Petzinger E, 2005: Frequency of the nt230 (del4) MDR1 mutation in Collies and related dog breeds in Germany. J Vet Pharmacol Therap, 28(6), 545-551.
- Geyer J, Janko C, 2012: Treatment of MDR1 mutant dogs with macrocyclic lactones. Curr pharm biotechnol, 13(6), 969-986.
- Gramer I, Leidolf R, Döring B, Klintzsch S, Krämer EM, Yalcin E, Petzinger E, Geyer J, 2011: Breed distribution of the nt230 (del4) MDR1 mutation in dogs. Vet J, 189(1), 67-71.
- Hall TA (1999). BioEdit: a user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT. In: Nucleic acids symposium series. (Vol. 41, No. 41), 95-98, Information Retrieval Ltd., London.
Hürlimann E, Hofmann D, Keiser J, 2023: Ivermectin and moxidectin against soil-transmitted helminth infections. Trends Parasitol, 39(4), 272-284.
- Janko C, Geyer J, 2013: Moxidectin has a lower neurotoxic potential but comparable brain penetration in P‐glycoprotein‐deficient CF‐1 mice compared to ivermectin. J Vet Pharmacol Ther, 36(3), 275-284.
Kawabata A, Momoi Y, Inoue-Murayama M, Iwasaki T, 2005: Canine mdr1 gene mutation in Japan. J vet med sci, 67(11), 1103-1107.
- Koban E, Saraç ÇG, Açan SC, Savolainen P, Togan İ, 2009: Genetic relationship between Kangal, Akbash and other dog populations. Discrete Appl Math, 157(10), 2335-2340.
- Koressaar T, Remm M, 2007: Enhancements and modifications of primer design program Primer3. Bioinformatics, 23(10), 1289-1291.
- Lerdkrai C, Phungphosop N, 2021: Prevalence of the MDR1 gene mutation in herding dog breeds and Thai Ridgebacks in Thailand. Vet World, 14(11), 3015-3020.
- Linardi RL, Natalini CC, 2006: Multi-drug resistance (MDR1) gene and P-glycoprotein influence on pharmacokinetic and pharmacodymanic of therapeutic drugs. Ciênc Rural, 36, 336-341.
- Löscher W, 2023: Is the antiparasitic drug ivermectin a suitable candidate for the treatment of epilepsy?. Epilepsia, 64(3), 553-566.
- Marelli SP, Polli M, Frattini S, Cortellari M, Rizzi R, Crepaldi P, 2020: Genotypic and allelic frequencies of MDR1 gene in dogs in Italy. Vet Rec Open, 7(1), e000375.
- Martinez M, Modric S, Sharkey M, Troutman L, Walker L, Mealey K, 2008: The pharmacogenomics of P‐glycoprotein and its role in veterinary medicine. J Vet Pharmacol Therap, 31(4), 285-300.
- 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, 727-33.
- Mealey KL, Meurs KM, 2008: Breed distribution of the ABCB1-1Δ (multidrug sensitivity) polymorphism among dogs undergoing ABCB1 genotyping. J Am Vet Med Assoc, 233(6), 921-924.
- Mealey KL, Owens JG, Freeman E, 2023: Canine and feline P‐glycoprotein deficiency: What we know and where we need to go. J Vet Pharmacol Therap, 46(1), 1-16.
- Ministry of Agriculture and Rural Affairs, 2009: Türkiye Evcil Hayvan Genetik Kaynakları Tanıtım Kataloğu. Birinci Basım. http://www.tarim.gov.tr/TAGEM/Belgeler/yayin/Katalog%20T%C3%BCrk%C3%A7e.pdf
- Monobe MM, Junior JPA, Lunsford KV, Silva RC, Bulla C, 2015: Frequency of the MDR1 mutant allele associated with multidrug sensitivity in dogs from Brazil. Vet Med (Auckl), 6, 111-117.
- Monobe MM, Lunsford KV, Araújo Júnior JP, Bulla C, 2013: Detection of heterozygous MDR1 nt230 (del4) mutation in a mixed-breed dog: case report of possible doxorubicin toxicosis. Vet Med, 4, 35-38.
- Tappin S, Goodfellow M, Peters I, Day M, Hall E, Mealey K, 2012: Frequency of the mutant MDR1 allele in dogs in the UK. Vet Rec, 171(72), 10.1136.
- Tepeli C, Çetin O, İnal Ş, Kırıkçı K, Yılmaz A, 2003: Kangal ve Akbaş Irkı Türk Çoban Köpeklerinde Büyüme Özellikleri. Turk J Vet Anim Sci, 27(4), 1011-1018.
- Turner T, 2005: Priscribing for dogs, Priscribing for cats In: The Veterinary Formulary, Bishop Y (Ed), (Sixth Edt.), 43-45, Pharmaceutical Press, London.
- Upadhyay S, Shrivastava S, Kumar D, Kabra A, Baghel US, 2019: Pharmacoepidemiology: A review. AJPRD, 7(2), 83-87.
- Yıldırım A, 2012: Kangal Irkı Köpeklerde Büyüme ve Beden Ölçülerine ait Özellikler. J Inst Sci Tech, 2(3), 117-126.
Yilmaz O, Aktan S, Ertugrul M, 2012: Türkiye yerli ve yeni köpek ırkları. In: International Animal Science Congress of Turkish and Relatives Communities. pp: 39-52.
- Yilmaz O, Sireli HD, Ertugrul M, 2015: The shepherd dog breeds in Turkey: a survey. ROAVS, 5(4), 172-177.