BIOMAT Database Logo BIOMAT Database Logo

The feline bile salt export pump: a structural and functional comparison with canine and human Bsep/BSEP. 2013

Cyrina D van Beusekom, and Jeroen J M W van den Heuvel, and Jan B Koenderink, and Johannes A Schrickx, and Frans G M Russel

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. CONCLUSIONS 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.

UI MeSH Term Description Entries
D008099 Liver A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances. Livers
D008107 Liver Diseases Pathological processes of the LIVER. Liver Dysfunction,Disease, Liver,Diseases, Liver,Dysfunction, Liver,Dysfunctions, Liver,Liver Disease,Liver Dysfunctions
D008969 Molecular Sequence Data Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories. Sequence Data, Molecular,Molecular Sequencing Data,Data, Molecular Sequence,Data, Molecular Sequencing,Sequencing Data, Molecular
D002415 Cats The domestic cat, Felis catus, of the carnivore family FELIDAE, comprising over 30 different breeds. The domestic cat is descended primarily from the wild cat of Africa and extreme southwestern Asia. Though probably present in towns in Palestine as long ago as 7000 years, actual domestication occurred in Egypt about 4000 years ago. (From Walker's Mammals of the World, 6th ed, p801) Felis catus,Felis domesticus,Domestic Cats,Felis domestica,Felis sylvestris catus,Cat,Cat, Domestic,Cats, Domestic,Domestic Cat
D003001 Cloning, Molecular The insertion of recombinant DNA molecules from prokaryotic and/or eukaryotic sources into a replicating vehicle, such as a plasmid or virus vector, and the introduction of the resultant hybrid molecules into recipient cells without altering the viability of those cells. Molecular Cloning
D004285 Dogs The domestic dog, Canis familiaris, comprising about 400 breeds, of the carnivore family CANIDAE. They are worldwide in distribution and live in association with people. (Walker's Mammals of the World, 5th ed, p1065) Canis familiaris,Dog
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000074020 ATP Binding Cassette Transporter, Subfamily B, Member 11 ATP-binding cassette, subfamily B, protein (P-glycoproteins) that functions in the ATP-dependent secretion of BILE SALTS into the BILE CANALICULI of HEPATOCYTES. Mutations in the ABCB11 gene are associated with progressive familial intrahepatic cholestasis 2 (see CHOLESTASIS, INTRAHEPATIC). ABCB11 Protein,ATP Binding Cassette Subfamily B Member 11,ATP Binding Cassette Transporter, Sub-Family B, Member 11,BSEP Protein,Bile Salt Export Pump
D000595 Amino Acid Sequence The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION. Protein Structure, Primary,Amino Acid Sequences,Sequence, Amino Acid,Sequences, Amino Acid,Primary Protein Structure,Primary Protein Structures,Protein Structures, Primary,Structure, Primary Protein,Structures, Primary Protein
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia

Related Publications

Cyrina D van Beusekom, and Jeroen J M W van den Heuvel, and Jan B Koenderink, and Johannes A Schrickx, and Frans G M Russel
Cloning of the dog bile salt export pump (BSEP; ABCB11) and functional comparison with the human and rat proteins.
November 2008, Biopharmaceutics & drug disposition,
Cyrina D van Beusekom, and Jeroen J M W van den Heuvel, and Jan B Koenderink, and Johannes A Schrickx, and Frans G M Russel
Structure based classification for bile salt export pump (BSEP) inhibitors using comparative structural modeling of human BSEP.
June 2017, Journal of computer-aided molecular design,
Cyrina D van Beusekom, and Jeroen J M W van den Heuvel, and Jan B Koenderink, and Johannes A Schrickx, and Frans G M Russel
The bile salt export pump (BSEP) in health and disease.
December 2012, Clinics and research in hepatology and gastroenterology,
Cyrina D van Beusekom, and Jeroen J M W van den Heuvel, and Jan B Koenderink, and Johannes A Schrickx, and Frans G M Russel
Polymorphic variants in the human bile salt export pump (BSEP; ABCB11): functional characterization and interindividual variability.
January 2010, Pharmacogenetics and genomics,
Cyrina D van Beusekom, and Jeroen J M W van den Heuvel, and Jan B Koenderink, and Johannes A Schrickx, and Frans G M Russel
Bile salt export pump (BSEP/ABCB11): trafficking and sorting disturbances.
July 2013, Current molecular pharmacology,
Cyrina D van Beusekom, and Jeroen J M W van den Heuvel, and Jan B Koenderink, and Johannes A Schrickx, and Frans G M Russel
Biosynthesis and trafficking of the bile salt export pump, BSEP: therapeutic implications of BSEP mutations.
June 2014, Molecular aspects of medicine,
Cyrina D van Beusekom, and Jeroen J M W van den Heuvel, and Jan B Koenderink, and Johannes A Schrickx, and Frans G M Russel
Bile salt excretion in skate liver is mediated by a functional analog of Bsep/Spgp, the bile salt export pump.
January 2000, American journal of physiology. Gastrointestinal and liver physiology,
Cyrina D van Beusekom, and Jeroen J M W van den Heuvel, and Jan B Koenderink, and Johannes A Schrickx, and Frans G M Russel
Current Concepts in Drug-Induced Bile Salt Export Pump (BSEP) Interference.
August 2014, Current protocols in toxicology,
Cyrina D van Beusekom, and Jeroen J M W van den Heuvel, and Jan B Koenderink, and Johannes A Schrickx, and Frans G M Russel
The canalicular bile salt export pump BSEP (ABCB11) as a potential therapeutic target.
May 2011, Current drug targets,
Cyrina D van Beusekom, and Jeroen J M W van den Heuvel, and Jan B Koenderink, and Johannes A Schrickx, and Frans G M Russel
Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11).
December 2013, Toxicological sciences : an official journal of the Society of Toxicology,
Copied contents to your clipboard!