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Pharmacogenomics of poor drug metabolism in Greyhounds: Cytochrome P450 (CYP) 2B11 genetic variation, breed distribution, and functional characterization.

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  • معلومة اضافية
    • المصدر:
      Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE
    • بيانات النشر:
      Original Publication: London : Nature Publishing Group, copyright 2011-
    • الموضوع:
      Genetic Variation*; Aryl Hydrocarbon Hydroxylases/*metabolism ; Cytochrome P450 Family 2/*metabolism ; Pharmacogenetics/*methods ; Steroid Hydroxylases/*metabolism; 3' Untranslated Regions ; Alleles ; Anesthetics, Intravenous/metabolism ; Animals ; Aryl Hydrocarbon Hydroxylases/genetics ; Breeding ; Cytochrome P450 Family 2/genetics ; Dogs ; Gene Frequency ; Haplotypes ; Linkage Disequilibrium ; Liver/enzymology ; Liver/metabolism ; Microsomes, Liver/metabolism ; Propofol/metabolism ; RNA Splicing ; Recombinant Proteins/biosynthesis ; Recombinant Proteins/isolation & purification ; Steroid Hydroxylases/genetics
    • نبذة مختصرة :
      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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    • Grant Information:
      R01 GM102130 United States GM NIGMS NIH HHS
    • الرقم المعرف:
      0 (3' Untranslated Regions)
      0 (Anesthetics, Intravenous)
      0 (Recombinant Proteins)
      EC 1.14.- (Steroid Hydroxylases)
      EC 1.14.14.1 (Aryl Hydrocarbon Hydroxylases)
      EC 1.14.14.1 (Cytochrome P450 Family 2)
      EC 1.14.14.1 (cytochrome P-450 CYP2B11 (dog))
      YI7VU623SF (Propofol)
    • الموضوع:
      Date Created: 20200111 Date Completed: 20201110 Latest Revision: 20241207
    • الموضوع:
      20241209
    • الرقم المعرف:
      PMC6952448
    • الرقم المعرف:
      10.1038/s41598-019-56660-z
    • الرقم المعرف:
      31919457