Organo anion transporter family


Members of the Organo Anion Transporter Family 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 and the major facilitator superfamily.
The generalized transport reactions catalyzed by members of the OAT family are:
Anion → Anion
Anion1 + Anion2 → Anion1 + Anion2

Function

Proteins of the OAT family catalyze the Na+-independent facilitated transport of fairly large amphipathic organic anions, such as bromosulfobromophthalein, prostaglandins, conjugated and unconjugated bile acids, steroid conjugates, thyroid hormones, anionic oligopeptides, drugs, toxins and other xenobiotics. One family member, OATP2B1, has been shown to use cytoplasmic glutamate as the exchanging anion. Among the well characterized substrates are numerous drugs including statins, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, antibiotics, antihistaminics, antihypertensives and anticancer drugs. Other substrates include luciferin, thyroid hormones and quinolones.
Organic anion transporting polypeptides carry bile acids as well as bilirubin and numerous hormones such as thyroid and steroid hormones across the basolateral membrane in hepatocytes, for excretion in bile. 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. Some of these have also been reported as inhibitors of certain OATPs: pazopanib and nilotinib against OATP-1B1 and vandetanib against OATP-1B3.
They also transport the dye bromosulphopthalein, availing it as a liver-testing substance.

Homology

The various paralogues in a mammal have differing but overlapping substrate specificities and tissue distributions as summarized by Hagenbuch and Meier. 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. As also shown by Hagenbuch and Meier, all but one of the mammalian homologues cluster together, separately from all other animal homologues.
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 correct.
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
SLCO1A2Solute carrier organic anion transporter family member 1A2Ubiquitous
SLCO1B1Solute carrier organic anion transporter family member 1B1Liver
SLCO1B3Solute carrier organic anion transporter family member 1B3Liver
SLCO1C1Solute carrier organic anion transporter family member 1C1Brain, testis
SLCO2A1Solute carrier organic anion transporter family member 2A1Ubiquitous
SLCO2B1Solute carrier organic anion transporter family member 2B1Ubiquitous
SLCO3A1Solute carrier organic anion transporter family member 3A1Testis, brain, heart, lung, spleen
SLCO4A1Solute carrier organic anion transporter family member 4A1Heart, placenta, lung, liver
SLCO4C1Solute carrier organic anion transporter family member 4C1Kidney
SLCO5A1Solute carrier organic anion transporter family member 5A1Breast, fetal brain, prostate
SLCO6A1Solute 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. The OATPs most associated with these interactions are OATP1B1, OATP1B3 and OATP2B1, which are all present on the hepatocyte basolateral 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. 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 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. Both OATP activation and inhibition has been observed and an in silico model for structure-based identification of OATP modulation was developed.
Since tyrosine kinase inhibitors 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.
Along with the organic anion transporters, organic cation transporters and the ATP-binding cassette transporters, the OATPs play an important role in the absorption, distribution, metabolism and exretion 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, suggesting that their evolution was early in the formation of the animal kingdom.