The feline bile salt export pump: a structural and functional comparison with canine and human Bsep/BSEP

BMC Veterinary Research

Frans GM Russel¹  Johannes A Schrickx²  Jan B Koenderink¹  Jeroen JMW van den Heuvel¹  Cyrina D van Beusekom² 

[1] Department of Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, Geert Grooteplein 28, Nijmegen 6500 HB, The Netherlands;Veterinary Pharmacology, Pharmacotherapy and Toxicology, Institute for Risk Assessment Sciences, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 104, Utrecht 3584 CM, The Netherlands

关键词: Inhibitor;    Bile acids;    Toxicity;    Drugs;    Liver;    Dog;    Cat;    Transporter;    ABCB11;    BSEP;   

Others  :  1119379
DOI  :  10.1186/1746-6148-9-259

 received in 2013-09-04, accepted in 2013-12-11,  发布年份 2013

【 摘 要 】

Background

The bile salt export pump (BSEP/ABCB11) is the primary transporter for the excretion of bile acids from hepatocytes into bile. In human, inhibition of BSEP by drugs has been related to drug-induced cholestasis and subsequent cytotoxic effects. The role of BSEP in canine and feline liver diseases has not been studied in detail, but the same mechanism of inhibition by drugs as in humans could play a role in veterinary medicine. The aim of this study was to investigate the functional characteristics of feline Bsep in comparison with canine and human Bsep/BSEP with respect to substrate affinities and inhibitory potential of model drugs. Orthologs of all three species were cloned and cell membrane vesicles overexpressing feline, canine and human Bsep/BSEP were prepared for functional analyses.

Results

The cDNA sequences of the open reading frames of feline, canine and human Bsep/BSEP showed a high similarity between the species. Functional studies demonstrated for all species a tendency to a higher affinity of BSEP/Bsep for the conjugated bile acid taurocholic acid (TCA) than glycocholic acid (GCA), and a higher affinity for GCA than for the unconjugated cholic acid (CA). The inhibitory potency of the model inhibitors cyclosporine A, troglitazone and ketoconazole was characterized against TCA uptake into BSEP/Bsep containing membrane vesicles. All three substances potently inhibited TCA uptake without significant species differences.

Conclusion

Structure and functional characteristics of cat, dog and human Bsep/BSEP appeared to be very similar, indicating that the properties of this transporter have been highly preserved among the different species. Therefore, inhibition of BSEP by drugs could also be a mechanism in cholestasis and liver disease in veterinary relevant animal species. This model could be used to predict drug-induced liver injury caused by BSEP inhibition at an early stage in veterinary drug development.

【 授权许可】

   
2013 van Beusekom et al.; licensee BioMed Central Ltd.

【 图 表 】

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