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Pharmacogenomics of poor drug metabolism in Greyhounds: Cytochrome P450 (CYP) 2B11 genetic variation, breed distribution, and functional characterization.
Martinez, Stephanie E; Andresen, Marie C; Zhu, Zhaohui; Papageorgiou, Ioannis; Court, Michael H.
Afiliación
  • Martinez SE; Comparative Pharmacogenomics Laboratory, Program in Individualized Medicine (PrIMe), Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, Washington, United States of America. s_martinez@wsu.edu.
  • Andresen MC; Comparative Pharmacogenomics Laboratory, Program in Individualized Medicine (PrIMe), Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, Washington, United States of America.
  • Zhu Z; Comparative Pharmacogenomics Laboratory, Program in Individualized Medicine (PrIMe), Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, Washington, United States of America.
  • Papageorgiou I; Comparative Pharmacogenomics Laboratory, Program in Individualized Medicine (PrIMe), Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, Washington, United States of America.
  • Court MH; Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, Diabetes Institute, University of Florida, Gainesville, Florida, United States of America.
Sci Rep ; 10(1): 69, 2020 01 09.
Article en En | MEDLINE | ID: mdl-31919457
Greyhounds recover more slowly from certain injectable anesthetics than other dog breeds. Previous studies implicate cytochrome P450 (CYP) 2B11 as an important clearance mechanism for these drugs and suggest Greyhounds are deficient in CYP2B11. However, no CYP2B11 gene mutations have been identified that explain this deficiency in Greyhounds. The objectives of this study were to provide additional evidence for CYP2B11 deficiency in Greyhounds, determine the mechanisms underlying this deficiency, and identify CYP2B11 mutations that contribute to this phenotype in Greyhounds. Greyhound livers metabolized CYP2B11 substrates slower, possessed lower CYP2B11 protein abundance, but had similar or higher mRNA expression than other breeds. Gene resequencing identified three CYP2B11 haplotypes, H1 (reference), H2, and H3 that were differentiated by mutations in the gene 3'-untranslated region (3'-UTR). Compared with 63 other dog breeds, Greyhounds had the highest CYP2B11-H3 allele frequency, while CYP2B11-H2 was widely distributed across most breeds. Using 3'-UTR luciferase reporter constructs, CYP2B11-H3 showed markedly lower gene expression (over 70%) compared to CYP2B11-H1 while CYP2B11-H2 expression was intermediate. Truncated mRNA transcripts were observed in CYP2B11-H2 and CYP2B11-H3 but not CYP2B11-H1 transfected cells. Our results implicate CYP2B11 3'-UTR mutations as a cause of decreased CYP2B11 enzyme expression in Greyhounds through reduced translational efficiency.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Farmacogenética / Esteroide Hidroxilasas / Variación Genética / Hidrocarburo de Aril Hidroxilasas / Familia 2 del Citocromo P450 Límite: Animals Idioma: En Revista: Sci Rep Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Farmacogenética / Esteroide Hidroxilasas / Variación Genética / Hidrocarburo de Aril Hidroxilasas / Familia 2 del Citocromo P450 Límite: Animals Idioma: En Revista: Sci Rep Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido