Organo anion transporter family

Last updated
Organic-anion-transporting polypeptide (OATP) family
Identifiers
SymbolOATP
Pfam PF03137
InterPro IPR004156
TCDB 2.A.60
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

Members of the Organic 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]

Contents

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.

AbbreviationProtein NameLocation
SLCO1A2 Solute carrier organic anion transporter family member 1A2Ubiquitous
SLCO1B1 Solute carrier organic anion transporter family member 1B1Liver
SLCO1B3 Solute carrier organic anion transporter family member 1B3Liver
SLCO1C1 Solute carrier organic anion transporter family member 1C1Brain, testis
SLCO2A1 Solute carrier organic anion transporter family member 2A1Ubiquitous
SLCO2B1 Solute carrier organic anion transporter family member 2B1Ubiquitous
SLCO3A1 Solute carrier organic anion transporter family member 3A1Testis, brain, heart, lung, spleen
SLCO4A1 Solute carrier organic anion transporter family member 4A1Heart, placenta, lung, liver
SLCO4C1 Solute carrier organic anion transporter family member 4C1Kidney
SLCO5A1 Solute carrier organic anion transporter family member 5A1Breast, fetal brain, prostate
SLCO6A1 Solute carrier organic anion transporter family member 6A1Testes, 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.

Related Research Articles

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<span class="mw-page-title-main">Rotor syndrome</span> Medical condition

Rotor syndrome is a rare cause of mixed direct (conjugated) and indirect (unconjugated) hyperbilirubinemia, relatively benign, autosomal recessive bilirubin disorder characterized by non-hemolytic jaundice due to the chronic elevation of predominantly conjugated bilirubin.

<span class="mw-page-title-main">Nilotinib</span> Chemical compound

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<span class="mw-page-title-main">Vandetanib</span> Chemical compound

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<span class="mw-page-title-main">Multidrug resistance-associated protein 2</span> Protein found in humans

Multidrug resistance-associated protein 2 (MRP2) also called canalicular multispecific organic anion transporter 1 (cMOAT) or ATP-binding cassette sub-family C member 2 (ABCC2) is a protein that in humans is encoded by the ABCC2 gene.

<span class="mw-page-title-main">Solute carrier organic anion transporter family member 1B1</span> Protein found in humans

Solute carrier organic anion transporter family member 1B1 is a protein that in humans is encoded by the SLCO1B1 gene. Pharmacogenomic research indicates that genetic variations in this gene are associated with response to simvastatin. Clinical guidelines exist that can guide dosing of simvastatin based on SLCO1B1 gene variant using genotyping or whole exome sequencing.

<span class="mw-page-title-main">SLC22A8</span> Protein-coding gene in the species Homo sapiens

Solute carrier family 22 member 8, or organic anion transporter 3 (OAT3), is a protein that in humans is encoded by the SLC22A8 gene.

<span class="mw-page-title-main">Solute carrier organic anion transporter family member 1B3</span> Protein-coding gene in the species Homo sapiens

Solute carrier organic anion transporter family member 1B3 (SLCO1B3) also known as organic anion-transporting polypeptide 1B3 (OATP1B3) is a protein that in humans is encoded by the SLCO1B3 gene.

<span class="mw-page-title-main">Solute carrier organic anion transporter family member 1A2</span>

Solute carrier organic anion transporter family member 1A2 is a protein that in humans is encoded by the SLCO1A2 gene.

<span class="mw-page-title-main">Solute carrier organic anion transporter family member 2B1</span> Protein-coding gene in the species Homo sapiens

Solute carrier organic anion transporter family member 2B1 also known as organic anion-transporting polypeptide 2B1 (OATP2B1) is a protein that in humans is encoded by the gene SLCO2B1.

<span class="mw-page-title-main">Organic anion transporter 1</span> Protein-coding gene in the species Homo sapiens

The organic anion transporter 1 (OAT1) also known as solute carrier family 22 member 6 (SLC22A6) is a protein that in humans is encoded by the SLC22A6 gene. It is a member of the organic anion transporter (OAT) family of proteins. OAT1 is a transmembrane protein that is expressed in the brain, the placenta, the eyes, smooth muscles, and the basolateral membrane of proximal tubular cells of the kidneys. It plays a central role in renal organic anion transport. Along with OAT3, OAT1 mediates the uptake of a wide range of relatively small and hydrophilic organic anions from plasma into the cytoplasm of the proximal tubular cells of the kidneys. From there, these substrates are transported into the lumen of the nephrons of the kidneys for excretion. OAT1 homologs have been identified in rats, mice, rabbits, pigs, flounders, and nematodes.

<span class="mw-page-title-main">SLC22A25</span> Protein-coding gene in the species Homo sapiens

Solute carrier family 22 member 25 (SLC22A25), also known as organic anion transporter UST6, is a protein that in humans is encoded by the SLC22A25 gene.

<span class="mw-page-title-main">Canertinib</span> Chemical compound

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<span class="mw-page-title-main">Solute carrier organic anion transporter family member 2A1</span> Protein-coding gene in the species Homo sapiens

Solute carrier organic anion transporter family member 2A1, also known as the prostaglandin transporter (PGT), is a protein that in humans is encoded by the SLCO2A1 gene.

This family of proteins are found both in prokaryotes and eukaryotes. In mammals, they are transmembrane proteins with functions in the liver and in the intestine. They are members of the solute carrier family of cotransporter genes which include SLC10A1 and SLC10A2.

Members of the organic solute transporter (OST) family have been characterized from a small bottom feeding species of fish called the little skate, Raja erinacea. Members have also been characterized from humans and mice. The OST family is a member of the larger group of secondary carriers, the APC superfamily.

<span class="mw-page-title-main">Solute carrier organic anion transporter family member 4c1</span> Mammalian protein found in Homo sapiens

Solute carrier organic anion transporter family member 4C1 is a protein that in humans is encoded by the SLCO4C1 gene, which is located on chromosome 5q21. The OATP4C1 protein is expressed in the basolateral membrane of the nephron of the human kidney, where it is involved in the uptake of organic anions for elimination in the urine. The drug digoxin is an important substrate of this transporter.

Renal tubular transport inhibitors are a class of drugs that interfere with the function of specific transporters in the renal proximal tubules, affecting the excretion and reabsorption of various substances, including drugs and endogenous compounds. These inhibitors target membrane transport proteins expressed in kidney tubule epithelial cells, which play a crucial role in drug elimination and can significantly influence drug pharmacokinetics. By modulating the activity of transporters such as organic anion transporters (OATs), organic cation transporters (OCTs), and multidrug and toxin extrusion proteins (MATEs), these inhibitors can alter the renal clearance of drugs, potentially leading to clinically significant drug-drug interactions (DDIs) and changes in drug efficacy or toxicity. Renal tubular transport inhibitors have both therapeutic applications, such as enhancing the efficacy of certain medications or reducing drug-induced nephrotoxicity, and potential risks, including unwanted drug accumulation and altered pharmacokinetics of co-administered drugs.

References

  1. ↑ Hagenbuch B, Meier PJ (February 2004). "Organic anion transporting polypeptides of the OATP/ SLC21 family: phylogenetic classification as OATP/ SLCO superfamily, new nomenclature and molecular/functional properties" (PDF). Pflügers Archiv. 447 (5): 653–65. doi:10.1007/s00424-003-1168-y. PMID   14579113. S2CID   21837213.
  2. 1 2 Hong W, Wu Z, Fang Z, Huang J, Huang H, Hong M (December 2015). "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. doi:10.1021/acs.molpharmaceut.5b00466. PMID   26562723.
  3. ↑ Lofthouse EM, Brooks S, Cleal JK, Hanson MA, Poore KR, O'Kelly IM, Lewis RM (October 2015). "Glutamate cycling may drive organic anion transport on the basal membrane of human placental syncytiotrophoblast". The Journal of Physiology. 593 (20): 4549–59. doi:10.1113/JP270743. PMC   4606536 . PMID   26277985.
  4. 1 2 3 4 Hagenbuch B, Stieger B (2013-06-01). "The SLCO (former SLC21) superfamily of transporters". Molecular Aspects of Medicine. 34 (2–3): 396–412. doi:10.1016/j.mam.2012.10.009. PMC   3602805 . PMID   23506880.
  5. ↑ Sugiyama D, Kusuhara H, Taniguchi H, Ishikawa S, Nozaki Y, Aburatani H, Sugiyama Y (October 2003). "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. doi: 10.1074/jbc.M306933200 . PMID   12923172.
  6. ↑ Patrick PS, Lyons SK, Rodrigues TB, Brindle KM (October 2014). "Oatp1 enhances bioluminescence by acting as a plasma membrane transporter for D-luciferin". Molecular Imaging and Biology. 16 (5): 626–34. doi:10.1007/s11307-014-0741-4. PMC   4161938 . PMID   24798747.
  7. 1 2 Pages 980-990 in:Walter F. Boron (2003). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. p. 1300. ISBN   1-4160-2328-3.
  8. 1 2 3 Khurana V, Minocha M, Pal D, Mitra AK (March 2014). "Role of OATP-1B1 and/or OATP-1B3 in hepatic disposition of tyrosine kinase inhibitors". Drug Metabolism and Drug Interactions. 29 (3): 179–90. doi:10.1515/dmdi-2013-0062. PMC   4407685 . PMID   24643910.
  9. ↑ Khurana V, Minocha M, Pal D, Mitra AK (May 2014). "Inhibition of OATP-1B1 and OATP-1B3 by tyrosine kinase inhibitors". Drug Metabolism and Drug Interactions. 29 (4): 249–59. doi:10.1515/dmdi-2014-0014. PMC   4407688 . PMID   24807167.
  10. ↑ Annaert P, Ye ZW, Stieger B, Augustijns P (March 2010). "Interaction of HIV protease inhibitors with OATP1B1, 1B3, and 2B1" (PDF). Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 40 (3): 163–76. doi:10.3109/00498250903509375. PMID   20102298. S2CID   207426839.
  11. ↑ De Bruyn T, Fattah S, Stieger B, Augustijns P, Annaert P (November 2011). "Sodium fluorescein is a probe substrate for hepatic drug transport mediated by OATP1B1 and OATP1B3". Journal of Pharmaceutical Sciences. 100 (11): 5018–30. doi:10.1002/jps.22694. PMID   21837650.
  12. ↑ De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP (June 2013). "Structure-based identification of OATP1B1/3 inhibitors". Molecular Pharmacology. 83 (6): 1257–67. doi:10.1124/mol.112.084152. PMID   23571415. S2CID   10627787.
  13. ↑ Torrie LS, Radford JC, Southall TD, Kean L, Dinsmore AJ, Davies SA, Dow JA (September 2004). "Resolution of the insect ouabain paradox". Proceedings of the National Academy of Sciences of the United States of America. 101 (37): 13689–93. Bibcode:2004PNAS..10113689T. doi: 10.1073/pnas.0403087101 . PMC   518814 . PMID   15347816.


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