2.A.60 The Organo Anion Transporter (OAT) Family
Proteins of the OAT family (solute carrier family 21 (previously called SLC21A; more recently designated SLCO by the HUGO Gene Nomenclature Committee) 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, respectively), steroid conjugates such as estrone-sulfate and dehydroepiandrosterone-sulfate (Rižner et al. 2017), thyroid hormones, anionic oligopeptides, drugs, toxins and other xenobiotics (Hong 2013). Among the well characterized substrates are numerous drugs including
statins, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, antibiotics,
antihistaminics, antihypertensives and anticancer drugs (Hagenbuch and Stieger 2013). There are six mammalian OAT families (Hagenbuch and Stieger 2013). Fluorescein is a general OAT family substrate (Patik et al. 2015), but Hagenbuch and Gui 2008 have summarized the
general features and substrates of the eleven human OATPs, and Jetter and Kullak-Ublick 2019 have summarized the interplay between various transporters of drugs, xenobiotics and bile salts. Differences in the structures, tissue distribution, substrates, and roles in liver diseases of OATs have been reviewed (Li et al. 2019).
The various paralogues in a mammal have differing but overlapping substrate specificities and tissue distributions as summarized by Hagenbuch and Meier (2003). 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 (Hagenbuch and Meier, 2003). Therefore, these mammalian proteins are all included within a single subfamily of the TC system (TC #2.A.60.1). The detailed substrates transported and their affinities are presented by Hagenbuch and Meier (2003). 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.
These transporters have been characterized primarily in mammals, but characterized homologues are present in D. melanogaster (Eraly et al. 2004; Chahine et al. 2012), A. gambiae, and C. elegans. The mammalian OAT family proteins exhibit a high degree of tissue specificity. Mammalian homologues consist of 640-722 amino acyl residues and possess 12 TMSs. They may catalyze electrogenic anion uniport or more frequently, anion exchange. Conformational changes of the multispecific organic anion transporter 1 (OAT1/SLC22A6) has suggested a molecular mechanism for initial stages of drug and metabolite transport (Tsigelny et al., 2011). The OAT family is a distant family within the MFS. Regulation of expression and function of OATps has been described (Svoboda et al., 2011).
The generalized transport reaction catalyzed by members of the OAT family is:
Anion (in) → Anion (out)
Anion1 (in) + Anion2 (out) → Anion1 (out) + Anion2 (in).
This family belongs to the Major Facilitator (MFS) Superfamily.
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Organic anion transporter, Oatp1 (SLC21A1) (substrates: digoxin, bromosulfophthalein, conjugated (taurocholate) and unconjugated (cholate) bile salts; conjugated and unconjugated steroid hormones, eicosanoids, peptides, drugs, toxins, other organic anions (e.g., bilirubin, glucuronide) and organic cations (e.g., N-methylquinidine, rocuronium)) (Na+-independent)
Oatp1 of Rattus norvegicus
Brain Oat14 (SLC21A14) (transports bidirectionally thyroxine (T4; prothyroid hormone; Km=0.2 μM), triiodothyronine (T3; Km=1.2 μM), amphipathic organic anions such as 17-β-estradiol-D-17-β-glucuronide (Km=10 μM), cerivastatin (Km=1 μM) and troglitazone (Km=0.8 μM)) (Sugiyama et al., 2003)
Oat14 of Rattus norvegicus (NP_445893)
|2.A.60.1.11||OATP4C1 kidney (basolateral membrane of proximal tubule cells), organic anion transporter (transports cardiac glycosides [digoxin, Km=8 μM; ouabain, Km= 0.4 μM], thyroid hormones (thyroxine and triiodothyronine), cAMP, and methotrexate (Mikkaichi et al., 2004)||Animals||SLCO4C1 of Homo sapiens|
OATP8/OATP1B3 (SLC21A8, SLCO1B3, OAT1B3, LST2). The bile acid (cholic acid)/glutathione (GSH:bile acid = 2.1) exporter (Briz et al., 2006). Also transports the octapeptide, cholecystokinin (CCK-8) (Gui and Hagenbuch, 2008), the anticancer agent, methotrexate, the statin, rosuvastatin (Nigam 2015), and danoprevir (hepatitis C virus protease inhibitor) (Brennan et al. 2015). Forms homo and hetero oligomers, but the monomer is the active species (Zhang et al. 2017). It has been used as a dual reporter gene for fluorescence and magnetic resonance imaging (Wu et al. 2018). It mediates the Na+-independent
uptake of organic anions such as 17-beta-glucuronosyl estradiol,
taurocholate, triiodothyronine (T3), leukotriene C4,
dehydroepiandrosterone sulfate (DHEAS), methotrexate and
sulfobromophthalein (BSP). It is involved in the clearance of bile acids and
organic anions from the liver (van de Steeg et al. 2012). Gly45 and Phe555 in TMSs 1 and 10 are critical for activation by epigallocatechin gallate (Yue et al. 2019). Rare coding variants that cause changes of charged residues can have large effects on the function and expression of OAT1B3 (Liu et al. 2021).
SLCO1B3 of Homo sapiens
|2.A.60.1.13||Liver anion transporter OatP of the little skate (689aas) (Cai et al., 2002)||Animals||OatP of Leucoraja (Raja) erinacea (Q8UVG4)|
The Na+-independent organic anion transporter, OATP-A (OatP1, Oat1A2, OatP1A2, SLC21A3, SLCO1A2) of 670 aas. Transports various anions such as cholate and taurocholate as well as the quinolone antibacterial agents, levofloxacin and Ochratoxin (Ota) (Maeda et al., 2007; Qi et al. 2017). Also transports thyroid hormones. The transport of primary and secondary thyroid hormone transporters has been reviewed (Kinne et al., 2011). Transports luciferin, the substrate of
luciferase, the anticancer agent, methotrexate and the statin, rosuvastatin (Nigam 2015; Patrick et al. 2014). The bovine (Bos taurus) organic anion-transporting polypeptide Oatp1a2 (Slco1a2) has been cloned and characterized (Geyer et al. 2004).
SLCO1A2 of Homo sapiens
OAT family 1C1 protein, isoform 1, Oatp1c1; transports thyroid horomone and other organic anions (Westholm et al. 2010). (83% identical to 2.A.60.1.10). Primary and secondary thyroid hormone transporters have been reviewed (Kinne et al., 2011) and (Bernal et al. 2015). Together with MTC8 (TC# 2.A.1.13.10), OATP1C1 controls skeletal muscle regeneration (Mayerl et al. 2018).
SLCO1C1 of Homo sapiens
|2.A.60.1.16|| solute carrier organic anion transporter family, member 5A1||Animals||SLCO5A1 of Homo sapiens|
|2.A.60.1.17|| solute carrier organic anion transporter family, member 6A1||Animals||SLCO6A1 of Homo sapiens|
|2.A.60.1.18|| solute carrier organic anion transporter family, member 3A1||Animals||SLCO3A1 of Homo sapiens|
Solute carrier organic anion transporter family member, OATP2A1; SLCO2A1; (Prostaglandin uptake transporter, PGT) (Solute carrier family 21 member 1 or 2). Transports prostaglandins E2, F2α and D2 as well as throboxanes (TxB2), inorganic and organic anions, and it plays a role in F4-mediated neonatal diarrhoea. (Schuster 2002; Ohkura et al. 2014). A mutation in the PGT gene induces chronic enteropathy (Jimbo et al. 2020). It is electrogenic and uptake can be driven by the efflux of lactate. The system has been reviewed (Nakanishi et al. 2021). Recessive inheritance of SLCO2A1 mutations is associated with two refractory diseases, primary hypertrophic osteoarthropathy (PHO) and chronic enteropathy associated with SLCO2A1 (CEAS). SLCO2A1 is also a key component of the Maxi-Cl- channel, which regulates fluxes of inorganic and organic anions, including ATP. The bimodal function of SLCO2A1 as a transporter and an ion channel have been reviewed (Nakanishi et al. 2021).
SLCO2A1 of Homo sapiens
Prostaglandin transporter, Pgt or PGT (SLC21A2) (substrates: eicosanoids including several prostaglandins and thromboxanes). Prostaglandins (PGs) transported include PGE2 PGF and PGH2 (Chi and Schuster, 2010). Pgt is an important mediator of ovulation, and its inhibitors are
potential candidates for nonhormonal contraception (Yerushalmi et al. 2016). PGT is involved in the
clearance of PGE2 from the brain during the recovery phase of LPS-induced acute-phase responses (Hosotani et al. 2015).
Pgt of Rattus norvegicus
Solute carrier organic anion transporter family member 2B1 (Organic anion transporter B) (OATP-B, OAT2B1, OAT2B1 or OATP2B1) (Organic anion transporter polypeptide-related protein 2) (OATP-RP2) (OATPRP2) (Solute carrier family 21 member 9). Catalyzes anion exchange in the placenta with cytoplasmic glutamate as the probable exchanging anion (Lofthouse et al. 2015) as well as uptake of ochratoxin (OTA) (Qi et al. 2017). A trp residue in the middle of TMS11 is essential (Bian et al. 2016). TMSs 1, 2, 4 and 5 seem to form the substrate binding pocket, and TMS 1 is also essential for stability (Fang et al. 2018). The inhibitory effects of the main soy isoflavones (daidzin, daidzein, genistin, genistein, glycitin, glycitein, biochanin A, formononetin) and their metabolites formed in vivo (S-equol, O-desmethylangolensin) towards the human OATP2B1 transporter have been characterized (Navrátilová et al. 2018). Aglycones of soy isoflavones and the main biologically active metabolite S-equol were able to inhibit hOATP2B1-mediated transport with Ki values for most aglycones ranging from 1 to 20 muM (Navrátilová et al. 2018). An interaction between hyperforin and OATP2B1 contributes to hepatocellular and intestinal absorption of its substrates (Schäfer et al. 2019). Human (h) and rat (r) don't have the same characteristics. hOATP2B1, but not rOATP2B1, is involved in intestinal absorption. While bromosulfophthalein and atorvastatin were substrates of both transporters, the steroid sulfate conjugates estrone 3-sulfate (E1S), progesterone sulfate and dehydroepiandrosterone sulfate were only transported by hOATP2B1 (Hussner et al. 2021).
SLCO2B1 (OatP2B1) of Homo sapiens
Oat33Ea of 745 aas with 12 TMSs in a 3 + 3 + 3 + 3 arrangement.
Oat33Ea of Drosophila melanogaster
Oat homologue of 816 aas
Oat homologue of Aedes aegypti
Oatp1p1 steroid hormone transporter of 613 aas and 11 TMSs (Popovic et al. 2013). It exhibits broad substrate specificity,and substrates include environmental contaminants (Dragojević et al. 2020).
Oat1p1 of Danio rerio (Zebrafish) (Brachydanio rerio)
Organic anion transporter, Oatp of 733 (or 724) aas and 12 TMSs (Mulenga et al. 2008).
Oatp of Amblyomma americanum (Lone star tick)
facilitative organic anion carrier, Slco1a6 of 670 aas and 12 TMSs. Also called Kidney-specific organic anion-transporting polypeptide 5 (Oatp5). Transports bile acids such as taurocholic acid and other anionic compounds (Tian et al. 2015).
Oatp5 of Mus musculus
OATP1C1 of 710 aas and 12 TMSs. Transports pro-thyroid hormone T4 with high affinity (Nele Bourgeois et al. 2016).
OATP1C1 of Gallus gallus (Chicken)
Drosophila Malpighian tubule transporter, Oatp58Dc, of 789 aas and 12 TMSs (Eraly et al. 2004; Chahine et al. 2012).
Oatp of Drosophila melanogaster (Fruit fly)
Thyroid hormone transporter, OATP1C1, of 710 aas and 12 TMSs in a clear 3 + 3 + 3 + 3 arrangement (Zada et al. 2017).
OATP1C1 of Danio rerio (Zebrafish) (Brachydanio rerio)
LST-3TM12 (LST3; SLCO1B7 is a product of splicing of SLCO1B3 and SLCO1B7, and encodes a protein with 640 aas and 12 TMSs. LST-3TM12 mRNA was verified by polymerase chain reaction showing liver enriched expression (Malagnino et al. 2017). LST-3TM12 is expressed in the PM and ER of hepatocytes and is associated with enhanced cellular accumulation of dehydroepiandrosterone sulfate (Vmax 300 pmol/mg/min; Km 34 µM) and estradiol 17-beta-glucuronide (Vmax 30 µmol/ mg/min; Km 33 µM) (Malagnino et al. 2017). Sreedharan et al. 2011 examined the tissue distribution of this porter.
LST3 of Homo sapiens
Organic anion transporter, Oat3a (SLC21A7; Oatp1a5; Slco1a5; The mouse ortholog is Q91YY5) (substrates: thyroid hormones (triiodothyronine and thyroxine) cholate, taurocholate hormones and their conjugates, eicosanoids, other organic anions and cations). Mediates uptake of ciprofloxacin in mice (Arakawa et al. 2012). Also, microcystin-leucine arginine (MC-LR) enters gonadotropin-releasing hormone (GnRH) neurons and induces decline of serum GnRH levels, resulting in male reproductive toxicity via hypothalamic- pituitary-testis axis (Jin et al. 2019).
Oat3a of Rattus norvegicus
Organic anion transporter, OatK1 (SLC21A4) (substrates: bile salts, hormones and their conjugates, eicosanoids, toxins, drugs, methotrexate, zidovudine)
OatK1 of Rattus norvegicus
Organic anion transporter, OATP2, OAT1B1, SLCO1B1 or OATP1B1 (LST-1) (SLC21A6) (substrates: mono- and bis-glucuronosyl bilirubin, sulfobromophthalein, taurocholate (Km = 14 μM), estrone sulfate, dehydroepiandrosterone sulfate, estradiol-17 β-D-glucuronide and other conjugated steroids (i.e., estrone 3-sulfate), leukotriene C4, eicosanoids (i.e., prostaglandin E2, thromboxane B2, leucotriene C4 and leucotriene E4), thyroid hormones (i.e., thyroxine and triiodothyronine), other organic anions, drugs, β-lactam antibiotics, ochratoxin, xenobiotics, ouabain, valsartan and pravastatin). OatP-C/1B1(SLC21A) (Hogg et al. 2015; Qi et al. 2017). The bile acid (cholic acid) uptake transporter, OatP-C (transports cholic acid without symport with GSH) (Briz et al., 2006; Degorter et al., 2012). Amino acids in TMS2 essential for estrone-3-sulfate transport have been identified (Li et al., 2012). OATP1B1 exhibits polymorphism related to neonatal hyperbilirubinemia (Zhang et al. 2010). Tyr258 and Trp259 in TMS6 play different roles in substrate specificity (Huang et al. 2013). Cyclic ABP aromatic ring substituents like the chloro-phenyl-thio
groups increase their ability to inhibit OATP-mediated
transport (Herfindal et al. 2014). TMS11 influences substrate binding, stability and trafficking (Hong et al. 2015). Transports danoprevir (hepatitis C virus protease inhibitor) (Brennan et al. 2015). Residues have been identified that are involved in modulating transport
kinetics, and this participation strongly depends on the substrate used in the assay (Gruetz et al. 2016). A 336A mutant is detained in the Golgi apparatus and the Y338A mutant exhibited accelerated protein degradation compared to that of the wild-type, but conservative replacement of Y338 withphenylalanine resulted in recovery of uptake and expression. Thus, the NPXY motif between TMSs 6 and 7 is essential for stable localization of OATP1B1 in the plasma membrane (Wang et al. 2019). SLCO1B1 rs2291075 may be a genetic locus associated with tacrolimus metabolism (Wu et al. 2021). Leucine heptad motifs within TMSs affect the function and oligomerization (Ni et al. 2021). Deep mutational scanning (DMS) has been used to determine the functional effects of variants that have been observed in the SLCO1B1 gene (Zhang et al. 2021). TMSs 2, 4 and 11 appear to be crucial for proper membrane localization and function of OATP1B1. Four of the studied variants were identified as loss-of-function variants and as such could make the individual harboring these variants susceptible to altered pharmacokinetics and adverse effects of substrate drugs (Kiander et al. 2021).
SLCO1B1 of Homo sapiens
Mouse liver Oatp2 (Slco1a4, Oatp1a4) of 670 aas and 12 TMSs in a 3 + 3 + 3 + 3 + 3 arrangement. Substrates include estrone-3-sulfate, dehydroepiandrosterone sulfate, ouabain, β-lactam antibiotics, BQ-123, digoxin (Km = 5.7 μM), bromosulfophthalein but not taurocholate, rocuronium or deltorphin II. Also transports thyroid hormones. Primary and secondary thyroid hormone transporters have been reviewed (Kinne et al., 2011). They catalyze transport of substrate drugs with neuroprotective properties across the blook-brain barrier (BBB) (Abdullahi et al. 2017).
Oatp2 (SLC21A5) of Mus musculus
|2.A.60.1.7||Oat9 (SLC21A9) (transports bile salts, eicosanoids and drugs)||Animals||Oat9 of Rattus norvegicus|
Oat4 (SLC21A10). Transports bile salts, eicosanoids, urate, hormones and their conjugates, toxins and other anions. Functions in urate reabsorption across the renal appical membrane (Prestin et al. 2014).
Oat4 of Rattus norvegicus
|2.A.60.1.9||Oat12 (SLC21A12) (transports bile salts, hormones (T3) and eicosanoids (prostaglandin E2))||Animals||SLCO4A1 of Homo sapiens|