Biology:Organo anion transporter family
| Organic-anion-transporting polypeptide (OATP) family | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| Symbol | OATP | ||||||||
| Pfam | PF03137 | ||||||||
| InterPro | IPR004156 | ||||||||
| TCDB | 2.A.60 | ||||||||
| |||||||||
Members of the Organo Anion Transporter (OAT) Family (organic-anion-transporting polypeptides, OATP) are membrane transport proteins or 'transporters' that mediate the transport of mainly organic anions across the cell membrane. Therefore, OATPs are present in the lipid bilayer of the cell membrane, acting as the cell's gatekeepers. OATPs belong to the Solute Carrier Family (SLC) and the major facilitator superfamily.[1]
The generalized transport reactions catalyzed by members of the OAT family are:
Anion (in) → Anion (out)
Anion1 (in) + Anion2 (out) → Anion1 (out) + Anion2 (in)
Function
Proteins of the OAT family catalyze the Na+-independent facilitated transport of fairly large amphipathic organic anions (and less frequently neutral or cationic drugs), such as bromosulfobromophthalein, prostaglandins, conjugated and unconjugated bile acids (taurocholate and cholate), steroid conjugates, thyroid hormones, anionic oligopeptides, drugs, toxins and other xenobiotics.[2] One family member, OATP2B1, has been shown to use cytoplasmic glutamate as the exchanging anion.[3] Among the well characterized substrates are numerous drugs including statins, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, antibiotics, antihistaminics, antihypertensives and anticancer drugs.[4] Other substrates include luciferin, thyroid hormones and quinolones.[2][5][6]
Organic anion transporting polypeptides carry bile acids as well as bilirubin and numerous hormones such as thyroid and steroid hormones across the basolateral membrane (facing sinusoids) in hepatocytes, for excretion in bile.[7] As well as expression in the liver, OATPs are expressed in many other tissues on basolateral and apical membranes, transporting anions, as well as neutral and even cationic compounds. They also transport an extremely diverse range of drug compounds, ranging from anti-cancer, antibiotic, lipid lowering to anti-diabetic drugs, as well as toxins and poisons.
Various anti-cancer drugs like pazopanib, vandetanib, nilotinib, canertinib and erlotinib are known to be transported via OATPs (OATP-1B1 and OATP-1B3).[8] Some of these have also been reported as inhibitors of certain OATPs: pazopanib and nilotinib against OATP-1B1 and vandetanib against OATP-1B3.[9]
They also transport the dye bromosulphopthalein, availing it as a liver-testing substance.[7]
Homology
The various paralogues in a mammal have differing but overlapping substrate specificities and tissue distributions as summarized by Hagenbuch and Meier.[4] These authors also provide a phylogenetic tree of the mammalian members of the family, showing that they fall into five recognizable subfamilies, four of which exhibit deep branching sub-subfamilies. However, all sequences within a subfamily are >60% identical while those between subfamilies are >40% identical.[4] As also shown by Hagenbuch and Meier, all but one (OatP4a1) of the mammalian homologues cluster together, separately from all other animal (insect and worm) homologues.[4]
OAT family homologues have been found in other animals but not outside of the animal kingdom. These transporters have been characterized in mammals, but homologues are present in Drosophila melanogaster, Anopheles gambiae, and Caenorhabditis elegans. The mammalian OAT family proteins exhibit a high degree of tissue specificity.
Human proteins
The table below shows the 11 known human OATPs. Note: Human OATPs are designated with capital letters, animal Oatps are designated with lower class letters. The 'SLCO' stands for their gene name; 'solute carrier organic anion.' Previous nomenclature using letters and numbers (e.g. OATP-A, OATP-8 is no longer used. The most well characterised human OATPs are OATP1A2, OATP1B1, OATP1B3 and OATP2B1. Very little is known about the function and characteristics of OATP5A1 and OATP6A1.
| Abbreviation | Protein Name | Location |
|---|---|---|
| SLCO1A2 | Solute carrier organic anion transporter family member 1A2 | Ubiquitous |
| SLCO1B1 | Solute carrier organic anion transporter family member 1B1 | Liver |
| SLCO1B3 | Solute carrier organic anion transporter family member 1B3 | Liver |
| SLCO1C1 | Solute carrier organic anion transporter family member 1C1 | Brain, testis |
| SLCO2A1 | Solute carrier organic anion transporter family member 2A1 | Ubiquitous |
| SLCO2B1 | Solute carrier organic anion transporter family member 2B1 | Ubiquitous |
| SLCO3A1 | Solute carrier organic anion transporter family member 3A1 | Testis, brain, heart, lung, spleen |
| SLCO4A1 | Solute carrier organic anion transporter family member 4A1 | Heart, placenta, lung, liver |
| SLCO4C1 | Solute carrier organic anion transporter family member 4C1 | Kidney |
| SLCO5A1 | Solute carrier organic anion transporter family member 5A1 | Breast, fetal brain, prostate |
| SLCO6A1 | Solute carrier organic anion transporter family member 6A1 | Testes, spleen, brain, placenta |
Pharmacology
The OATPs play a role in the transport of some classes of drugs across the cell membrane, particularly in the liver and kidney. In the liver, OATPs are expressed on the basolateral membrane of hepatocytes, transporting compounds into the hepatocyte for biotransformation. A number of drug-drug interactions have been associated with the OATPs, affecting the pharmacokinetics and pharmacodynamics of drugs. This is most commonly where one drug inhibits the transport of another drug into the hepatocyte, so that it is retained longer in the body (i.e. increased plasma half-life). The OATPs most associated with these interactions are OATP1B1, OATP1B3 and OATP2B1, which are all present on the hepatocyte basolateral (sinusoidal) membrane. OATP1B1 and OATP1B3 are known to play an important role in hepatic drug disposition. These OATPs contribute towards first step of hepatic accumulation and can influence the disposition of drug via hepatic route.[8] The most clinically relevant interactions have been associated with the lipid lowering drugs statins, which led to the removal of cerivastatin from the market in 2002. Single nucleotide polymorphisms (SNPs) are also associated with the OATPs; particularly OATP1B1.
Many modulators of OATP function have been identified based on in vitro research in OATP-transfected cell lines.[10][11] Both OATP activation and inhibition has been observed and an in silico model for structure-based identification of OATP modulation was developed.[12]
Since tyrosine kinase inhibitors (TKIs) are metabolized in the liver, interaction of TKIs with OATP1B1 and OATP1B3 can be considered as important molecular targets for transporter mediated drug-drug interactions.[8]
Along with the organic cation transporters and the ATP-binding cassette transporters, the OATPs play an important role in the absorption, distribution, metabolism and excretion (ADME) of many drugs.
Evolution
OATPs are present in many animals, including fruit flies, zebrafish, dogs, cows, rats, mice, monkeys and horses. OATPs are not present in bacteria, indicating their evolution from the animal kingdom. However homologs do not correlate well with the human OATPs and therefore it is likely that isoforms arose by gene duplication. OATPs have however been found in insects,[13] suggesting that their evolution was early in the formation of the animal kingdom.
References
- ↑ "Organic anion transporting polypeptides of the OATP/ SLC21 family: phylogenetic classification as OATP/ SLCO superfamily, new nomenclature and molecular/functional properties". Pflügers Archiv 447 (5): 653–65. February 2004. doi:10.1007/s00424-003-1168-y. PMID 14579113. http://doc.rero.ch/record/311573/files/424_2003_Article_1168.pdf.
- ↑ 2.0 2.1 "Amino Acid Residues in the Putative Transmembrane Domain 11 of Human Organic Anion Transporting Polypeptide 1B1 Dictate Transporter Substrate Binding, Stability, and Trafficking". Molecular Pharmaceutics 12 (12): 4270–6. December 2015. doi:10.1021/acs.molpharmaceut.5b00466. PMID 26562723.
- ↑ "Glutamate cycling may drive organic anion transport on the basal membrane of human placental syncytiotrophoblast". The Journal of Physiology 593 (20): 4549–59. October 2015. doi:10.1113/JP270743. PMID 26277985.
- ↑ 4.0 4.1 4.2 4.3 "The SLCO (former SLC21) superfamily of transporters". Molecular Aspects of Medicine 34 (2–3): 396–412. 2013-06-01. doi:10.1016/j.mam.2012.10.009. PMID 23506880.
- ↑ "Functional characterization of rat brain-specific organic anion transporter (Oatp14) at the blood-brain barrier: high affinity transporter for thyroxine". The Journal of Biological Chemistry 278 (44): 43489–95. October 2003. doi:10.1074/jbc.M306933200. PMID 12923172.
- ↑ "Oatp1 enhances bioluminescence by acting as a plasma membrane transporter for D-luciferin". Molecular Imaging and Biology 16 (5): 626–34. October 2014. doi:10.1007/s11307-014-0741-4. PMID 24798747.
- ↑ 7.0 7.1 Pages 980-990 in:Walter F. Boron (2003). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. pp. 1300. ISBN 1-4160-2328-3.
- ↑ 8.0 8.1 8.2 "Role of OATP-1B1 and/or OATP-1B3 in hepatic disposition of tyrosine kinase inhibitors". Drug Metabolism and Drug Interactions 29 (3): 179–90. March 2014. doi:10.1515/dmdi-2013-0062. PMID 24643910.
- ↑ "Inhibition of OATP-1B1 and OATP-1B3 by tyrosine kinase inhibitors". Drug Metabolism and Drug Interactions 29 (4): 249–59. May 2014. doi:10.1515/dmdi-2014-0014. PMID 24807167.
- ↑ "Interaction of HIV protease inhibitors with OATP1B1, 1B3, and 2B1". Xenobiotica; the Fate of Foreign Compounds in Biological Systems 40 (3): 163–76. March 2010. doi:10.3109/00498250903509375. PMID 20102298. http://www.zora.uzh.ch/id/eprint/32186/2/Stieger_Annaert_xenobioticaV.pdf.
- ↑ "Sodium fluorescein is a probe substrate for hepatic drug transport mediated by OATP1B1 and OATP1B3". Journal of Pharmaceutical Sciences 100 (11): 5018–30. November 2011. doi:10.1002/jps.22694. PMID 21837650.
- ↑ "Structure-based identification of OATP1B1/3 inhibitors". Molecular Pharmacology 83 (6): 1257–67. June 2013. doi:10.1124/mol.112.084152. PMID 23571415.
- ↑ "Resolution of the insect ouabain paradox". Proceedings of the National Academy of Sciences of the United States of America 101 (37): 13689–93. September 2004. doi:10.1073/pnas.0403087101. PMID 15347816. Bibcode: 2004PNAS..10113689T.
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