Members of the Organo Anion Transporter (OAT) Family (organic-anion-transporting polypeptides, OATP) are
membrane transport protein
A membrane transport protein (or simply transporter) is a membrane protein involved in the movement of ions, small molecules, and macromolecules, such as another protein, across a biological membrane. Transport proteins are integral transmembra ...
s or 'transporters' that mediate the transport of mainly organic
anion
An ion () is an atom or molecule with a net electrical charge.
The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...
s across the
cell membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
. 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
The major facilitator superfamily (MFS) is a superfamily of membrane transport proteins that facilitate movement of small solutes across cell membranes in response to chemiosmotic gradients.
Function
The major facilitator superfamily (MFS) are ...
.
The generalized transport reactions catalyzed by members of the OAT family are:
Anion (in) → Anion (out)
Anion
1 (in) + Anion
2 (out) → Anion
1 (out) + Anion
2 (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
File:Thyroid_system.svg, upright=1.5, The thyroid system of the thyroid hormones T3 and T4
rect 376 268 820 433 Thyroid-stimulating hormone
rect 411 200 849 266 Thyrotropin-releasing hormone
rect 297 168 502 200 Hypothalamus
rect 66 216 386 25 ...
, anionic oligopeptides, drugs, toxins and other
xenobiotic
A xenobiotic is a chemical substance found within an organism that is not naturally produced or expected to be present within the organism. It can also cover substances that are present in much higher concentrations than are usual. Natural compo ...
s.
One family member, OATP2B1, has been shown to use
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
ic glutamate as the exchanging anion. Among the well characterized substrates are numerous drugs including
statin
Statins, also known as HMG-CoA reductase inhibitors, are a class of lipid-lowering medications that reduce illness and mortality in those who are at high risk of cardiovascular disease. They are the most common cholesterol-lowering drugs.
Low ...
s,
angiotensin
Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the adren ...
-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 Epithelial polarity is one example of the cell polarity that is a fundamental feature of many types of cells. Epithelial cells feature distinct 'apical', 'lateral' and 'basal' plasma membrane domains. Epithelial cells connect to one another via t ...
(facing sinusoids) in
hepatocytes
A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass.
These cells are involved in:
* Protein synthesis
* Protein storage
* Transformation of carbohydrates
* Synthesis of cholesterol, ...
, for excretion in bile.
[Pages 980-990 in:] 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).
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
Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a s ...
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 (OatP4a1) of the mammalian homologues cluster together, separately from all other animal (insect and worm) homologues.
OAT family homologues have been found in other animals but not outside of the animal kingdom
Kingdom commonly refers to:
* A monarchy ruled by a king or queen
* Kingdom (biology), a category in biological taxonomy
Kingdom may also refer to:
Arts and media Television
* ''Kingdom'' (British TV series), a 2007 British television drama s ...
. These transporters have been characterized in mammals, but homologues are present in ''Drosophila melanogaster
''Drosophila melanogaster'' is a species of fly (the taxonomic order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the " vinegar fly" or "pomace fly". Starting with ...
, 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.
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 Biotransformation is the biochemical modification of one chemical compound or a mixture of chemical compounds. Biotransformations can be conducted with whole cells, their lysates, or purified enzymes. Increasingly, biotransformations are effected w ...
. 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. The most clinically relevant interactions have been associated with the lipid lowering drugs statins, which led to the removal of cerivastatin
Cerivastatin ( INN, brand names: Baycol, Lipobay) is a synthetic member of the class of statins used to lower cholesterol and prevent cardiovascular disease. It was marketed by the pharmaceutical company Bayer A.G. in the late 1990s, competing w ...
from the market in 2002. Single nucleotide polymorphisms (SNPs) are also associated with the OATPs; particularly OATP1B1
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. Clinica ...
.
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 (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.
Along with the organic cation transporters and the ATP-binding cassette transporter
The ATP synthase, ATP-binding cassette transporters (ABC transporters) are a transport system superfamily that is one of the largest and possibly one of the oldest gene family, gene families. It is represented in all extant taxon, extant Phylum ...
s, 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, suggesting that their evolution was early in the formation of the animal kingdom.
References
{{Solute carrier family, bg, bg3
Solute carrier family
Protein families
Membrane proteins
Transmembrane proteins
Transmembrane transporters
Transport proteins
Integral membrane proteins