Cambridge MedChem Consulting

Transporters

Not all passage across membranes is passive, there are a number of proteins involved in transporting molecules/ions into and out of cells, probably >350. Transporters probably exist in every membrane. Many were discovered after upregulation in drug-resistant tumor cells. It is possible to evaluate some transporters in in vitro systems (Caco-2, LLC-PK1:MDR1) See Absorption. Transporters can have an enormous influence on the absorption, distribution or elimination of a drug. The best understood is ABCB1 also known as P-gp, MDR1 (mdr1 in rodents) this transporter is present in the blood-brain barrier, in the gut, on hepatocytes, and the kidney. It is also one of the transporters found to be up-regulated in some drug-resistant tumors.

Major Human Transporters

Gene Aliases Tissue Substrate Inhibitor Inducer
ABCB1P-gp, MDR1 intestine, liver, kidney, brain, placenta, adrenal, testes digoxin, fexofenadine, indinavir, vincristine, colchicine. topotecan, paclitaxel ritonavir, cyclosporine, verapamil, erythromycin, ketocoanzole, itraconazole, quinidine, elacridar (GF120918) LY335979, valspodar (PSC 833) rifampin, St John’s Wort
ABCB4MDR3 liver digoxin, paclitaxel, vinblastine    
ABCB11BSEP liver vinblastine    
ABCC1MRP1 intestine, liver, kidney, brain adefovir, indinavir    
ABCC2MRP2, CMOAT intestine, liver, kidney, brain indinavir, cisplatin, cyclosporine  
ABCC3MRP3, CMOAT2 intestine, liver, kidney, placenta, adrenal etoposide, methotrexate, tenoposide    
ABCC4MRP4        
ABCC5MRP5        
ABCC6MRP6 liver, kidney cisplatin, daunorubicin    
ABCG2BCRP intestine, liver, breast, placenta daunorubicin, doxorubicin, topotecan, rosuvastatin, sulfasalazine elacridar (GF120918)  
SLCO1B1OATP1B1, OATP-C OATP2 liver rifampin, rosuvastatin, methotrexate, pravastatin, thyroxine cyclosporine rifampin  
SLCO1B3OATP1B3, OATP8, liver digoxin, methotrexate, rifampin,    
SLCO2B1SLC21A9, OATP-B intestine, liver, kidney, brain pravastatin    
SLC10A1NTCP liver, pancreas rosuvastatin    
SLC10A2ASBT ileum, kidney, biliary tract      
SLC15A1PEPT1 intestine, kidney ampicillin, amoxicillin, captopril, valacyclovir    
SLC15A2PEPT2 kidney ampicillin, amoxicillin, captopril, valacyclovir    
SLC22A1OCT-1 liver acyclovir, amantadine, desipramine, ganciclovir metformin disopyramide, midazolam, phenformin, phenoxy-benzamine quinidine, quinine, ritonavir, verapamil  
SLC22A2OCT2 kidney, brain amantadine, cimetidine, memantine desipramine, phenoxy-benzamine quinine  
SLC22A3OCT3 skeletal muscle, liver, placenta, kidney, heart cimetidine desipramine, prazosin, phenoxy-benzamine  
SLC22A4OCTN1 kidney, skeletal muscle, placenta, prostate, heart quinidine, verapamil    
SLC22A5OCTN2 kidney, skeletal muscle, prostate, lung, pancreas, heart, small intestine, liver quinidien, verapamil    
SLC22A6OAT1 kidney, brain acyclovir, adefovir, methotrexate, zidovudine probenecid, cefadroxil, cefamandole, cefazolin,  
SLC22A7OAT2 liver, kidney zidovudine    
SLC22A8OAT3 kidney, brain cimetidine, methotrexate, zidovudine probenecid, cefadroxil, cefamandole, cefazolin,  

ABC:ATP-binding cassette transporter superfamily; SLC: solute-linked carrier transporter family; SLCO: solute-linked carrier organic anion transporter family; MDR1: multi-drug resistance; MRP: multi-drug resistance related protein; BSEP:bile salt export pump; BCRP: breast cancer resistance protein; OAT: organic anion transporter; OCT: organic cation transporter; NTCP: sodium taurocholate co-transporting polypeptide; ASBT: apical sodium-dependent bile salt transporter.

Metrabase

The Metabolism and Transport Database (Metrabase) is a cheminformatics and bioinformatics resource that contains curated data related to human small molecule metabolism and transport, Journal of Cheminformatics 2015, 7:31 DOI. Currently it includes interaction data on 20 transporters, 3438 molecules and 11649 interaction records manually abstracted from 1211 literature references and supplemented with data from other resources as shown in the image below taken from the original publication.

s13321-015-0083-5-1

Metrabase is accessible via an online user interface at http://www-metrabase.ch.cam.ac.uk, and allows users to search the database by protein or compound. Search by protein is the main feature. It allows retrieval of all compounds interacting with the selected protein and shows their action types and links to the literature references from which the data originated. Search by compound allows name, structure, substructure and similarity searches. These are supported by the ChemDoodle 2D sketcher for structure drawing and the Mychem cartridge (for MySQL) , which performs cheminformatics-specific functions. The similarity search employs the FP2 fingerprint of Open Babel and the exact search compares InChI strings. Furthermore, users can retrieve tissue expression data and access information held in the UniProt and HGNC databases following the links provided in the list of the proteins. A database dump is also available for download enabling users to install their own local copy of the database. MySQL Workbench can be used as an interface: even though knowledge of SQL may not be required to display records of all tables and save them in other formats, such as TSV or CSV, it is needed to fully exploit the database in this manner.

Currently the database contains details for the following transporters, Name(Number of Compounds): ASBT (82), BCRP1 (980), GLUT1 (83), LAT1 (6), MCT1 (38), MDR1 (1,182), MRP1 (194), MRP2 (519), MRP3 (133), MRP4 (66), OATP1A2 (112), OATP1B1 (444), OATP1B3 (344), OATP2A1 (16), OATP2B1 (365), OATP3A1 (13), OATP4A1 (9), OCT1 (506), OSTA (0), OSTA/OSTB (6), OSTB (0), PEPT1 (475).

Worth looking at the Human Membrane Transporter Database.

ABCB1 in more detail

Updated 17 February 2012