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). OATP models share a conserved transmembrane helix folding harbouring a druggable binding pocket in the shape of an inner pore (Tonduru et al. 2022). Simulations suggest that the conserved salt bridges in the extracellular region between residues in TMS1 and TMS7 might influence the entrance of substrates. Interactions between residues in TMS1 and TMS4 within OATP1 family members have shown their importance in transport of substrates (Tonduru et al. 2022).

Animals

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)

Animals

Oat14 of Rattus norvegicus (NP_445893)

OATP4C1 (SLCO4C1, OATPX) 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, Ct-OAT1B3 isoform 1). 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). Val386 in TMS 8 is important for the activation of OATP1B3 by epigallocatechin gallate (Wang et al. 2022). Cancer-type organic anion-transporting polypeptide 1B3 (Ct-OATP1B3) is localized to lysosomes and mediates resistance against kinase inhibitors (Haberkorn et al. 2022). AmicroRNA (MiRNA) regulates the expression of OATP1B3 in mammalian cells (Shu et al. 2023).  G45 and V386 in TMSs 1 and 8 are critical for the activation of OATP1B3-mediated E17betaG uptake by clotrimazole (Han et al. 2024). SLCO1b3 and SLC25a41 can be used with the fulorescent probe to distinguish B-cells from T-cells (Cho et al. 2024).  This system is inhibited by various Canabis products (Anderson et al. 2022).

Animals

SLCO1B3 of Homo sapiens

The Na⁺-independent organic anion transporter, OATP-A (OatP1, Oat1A2, OatP1A2, SLC21A3, SLCO1A2) of 670 aas of 670 aas and 12 TMSs.  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 hormones 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).

Animals

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). Thyroid hormone transporters MCT8 and OATP1C1 are expressed in projection neurons and interneurons of basal ganglia and motor thalamus in adult human brains (Wang et al. 2023). Assays have been developed to screen chemicals for their capacity to inhibit thyroid hormone transmembrane transporter proteins, OATP1C1 and OAT4 (Wagenaars et al. 2024). Tetrabromobisphenol A (TBBPA) was identified as an OATP1C1 inhibitor, more potent than any of the reference chemicals tested, and perfluorooctanesulfonic acid (PFOS), perfluoroctanic acid (PFOA), pentachlorophenol and quercetin are OATP1C1 inhibitors in a similar range of potency to the reference chemicals tested. Bromosulfophthalein, TBBPA, PFOA and PFOS were identified as potent OAT4 inhibitors (Wagenaars et al. 2024).

Animals

SLCO1C1 of Homo sapiens

Solute carrier organic anion transporter family, member 3A1, of 710 aas and 12 TMSs in a 3 + 3 + 3 + 3 TMS arrangement.  Transport of aromatic amino acids, l-tryptophan, l-tyrosine, and l-phenylalanine, by the organic anion transporting polypeptide (OATP) 3A1 has been demonstrated (Surrer et al. 2024).  OATP3A1 (gene symbol SLCO3A1, Uniprot: Q9UIG8) is ubiquitously expressed in human cells and highly expressed in many cancer tissues and cell lines (Surrer et al. 2024). Specifically, OATP3A1-mediated transport of l-tryptophan, l-tyrosine, and l-phenylalanine with 194.8 ± 28.7% (P < 0.05), 226.2 ± 18.7% (P < 0.001), and 235.2 ± 13.5% (P < 0.001), respectively, in OATP3A1-overexpressing cells compared to control cells. Furthermore, kinetic transport parameters (K_m values) were determined (Trp = 61.5 ± 14.2 μm, Tyr = 220.8 ± 54.5 μm, Phe = 234.7 ± 20.6 μm).

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). Homozygous missense variants in the Solute Carrier Organic Anion Transporter 2A1 ( SLCO2A1) gene underlies isolated nail clubbing (Umair et al. 2023).

Animals

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).

Animals

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). SN-38 is absorbed into the enterocytes via OATP2B1, glucuronidated by UGTs to SN-38G, and excreted into the digestive tract lumen by MRP2 and BCRP. SN-38G can be deconjugated by β-glucuronidase from intestinal bacteria in the digestive tract lumen to regenerate SN-38 (Martha et al. 2023). Interplay of OATP1A/1B/2B1 uptake transporters and ABCB1 and ABCG2 efflux transporters are important in the handling of bilirubin and drugs (Li et al. 2024).

Animals

SLCO2B1 (OatP2B1) of Homo sapiens

Oat33Ea of 745 aas with 12 TMSs in a 3 + 3 + 3 + 3 arrangement.

Insects

Oat33Ea of Drosophila melanogaster

Oat homologue of 816 aas

Insects

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).

Animals

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).

Animals

Oat3a of Rattus norvegicus

Organic anion transporter, OatK1 (SLC21A4) (substrates: bile salts, hormones and their conjugates, eicosanoids, toxins, drugs, methotrexate, zidovudine)

Animals

OatK1 of Rattus norvegicus

Organic anion transporter, OATP2, OAT1B1, SLCO1B1 or OATP1B1, OATP2, (LST-1) (SLC21A6; S01) (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). Machine learning models have been used to identify novel inhibitors which include abamectin, asiaticoside, berbamine, doramectin, mobocertinib, and umbralisib (Lane et al. 2022). SLCO1B1 variants give rise to psychotic disorders (Häkkinen et al. 2023). The double-leucine motifs sffect internalization, stability, and function of OAT1B1 (Wang et al. 2023).  Dichlorofluorescein is transported by human OAT1B1 (Liu et al. 2024).  This system is inhibited by various canabis products (Anderson et al. 2022).

Animals

SLCO1B1 of Homo sapiens

Mouse liver Oatp2 (Slco1a4, Oatp1a4) of 670 aas and 12 TMSs in a 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 blood-brain barrier (BBB) (Abdullahi et al. 2017). DNA methylation plays an important role in regulating BBB repair after stroke, through regulating processes associated with BBB restoration (Phillips et al. 2023).

Animals

Oatp2 (SLC21A5) of Mus musculus

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).

Animals

Oat4 of Rattus norvegicus

Oat12 (SLC21A12) (transports bile salts, hormones (T₃) and eicosanoids (prostaglandin E₂)). It has 722 aas and 12 TMSs.  There is an interplay of OATP1A/1B/2B1 uptake transporters and ABCB1 and ABCG2 efflux transporters in the handling of bilirubin and drugs (Li et al. 2024).

Animals

SLCO4A1 of Homo sapiens