{"gene":"SLCO1A2","run_date":"2026-04-28T20:42:08","timeline":{"discoveries":[{"year":1999,"finding":"Human OATP1A2 (OATP-A) mediates cellular uptake of fexofenadine, as demonstrated using a recombinant vaccinia expression system; P-glycoprotein was identified as the efflux transporter for the same drug, and several P-gp inhibitors also inhibited OATP.","method":"Recombinant vaccinia expression system in cells; radiolabeled substrate uptake assay","journal":"Drug metabolism and disposition","confidence":"High","confidence_rationale":"Tier 1 — reconstituted transport activity in recombinant expression system with pharmacological inhibition controls","pmids":["10421612"],"is_preprint":false},{"year":2004,"finding":"OATP1A2 (OATP-A/SLC21A3) mediates influx transport of saquinavir (HIV protease inhibitor) in Xenopus laevis oocytes injected with OATP-A cRNA, with saturable kinetics (Km = 36.4 µM); in HepG2 hepatic cells, OATP-A substrates competitively inhibited saquinavir uptake, indicating OATP-A acts in concert with apical P-gp and MRP2 for vectorial hepatic transport.","method":"Xenopus laevis oocyte expression system; HepG2 cell uptake assays with pharmacological inhibitors; saturation kinetics","journal":"Molecular pharmaceutics","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in Xenopus oocytes plus functional validation in hepatic cells with multiple inhibitors","pmids":["15832500"],"is_preprint":false},{"year":2005,"finding":"OATP1A2 is expressed in human brain capillary endothelial cells and renal distal nephron as demonstrated by immunohistochemistry. Naturally occurring nonsynonymous SNPs in SLCO1A2 (A516C/E172D and A404T/N135I) markedly reduced transport of estrone 3-sulfate, deltorphin II, and DPDPE; reduced plasma membrane expression contributed to loss of function as shown by cell surface biotinylation and confocal microscopy. The A404T variant also showed altered glycosylation.","method":"Immunohistochemistry; in vitro transport assays in transfected cells; cell surface biotinylation; immunofluorescence confocal microscopy; SDS-PAGE for glycosylation analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including functional transport assay, surface biotinylation, microscopy, and glycosylation analysis in a single study","pmids":["15632119"],"is_preprint":false},{"year":2003,"finding":"OATP1A2 (OATP-A) mRNA was identified in human liver, placenta, and purified trophoblast cells by RT-PCR and sequencing; injection of OATP-A mRNA into Xenopus laevis oocytes conferred ability to take up unconjugated bilirubin (UCB), though with very low efficiency compared to OATP-8 and OATP-C.","method":"RT-PCR/sequencing; real-time quantitative RT-PCR; Xenopus laevis oocyte expression with radiolabeled substrate uptake and kinetic analysis","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 — reconstituted transport function in Xenopus oocytes with kinetic analysis","pmids":["12568656"],"is_preprint":false},{"year":2012,"finding":"Liver-specific humanized OATP1A2 transgenic mice showed partial rescue of increased plasma bilirubin and increased plasma levels of methotrexate seen in Slco1a/1b knockout mice; OATP1A2 (but not OATP1B1) significantly increased liver uptake of paclitaxel (2 mg/kg), demonstrating in vivo transport function of OATP1A2 for both organic anionic (methotrexate) and hydrophobic bulky (paclitaxel) substrates.","method":"Humanized transgenic mouse model (liver-specific OATP1A2 knockin in Slco1a/1b knockout background); pharmacokinetic analysis; tissue distribution measurement","journal":"Clinical cancer research","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic rescue experiment with pharmacokinetic readouts replicated across multiple substrate drugs","pmids":["23243220"],"is_preprint":false},{"year":2011,"finding":"Imatinib uptake was significantly enhanced in OATP1A2-transfected HEK293 cells; naringin (an OATP1A2 inhibitor) decreased imatinib transport in OATP1A2-transfected HEK293 cells, human intestinal Caco-2 cells, and K562 CML cells, establishing OATP1A2 as a transporter of imatinib into cells.","method":"HEK293 transfection uptake assay; pharmacological inhibition with naringin in multiple cell lines","journal":"Clinical pharmacology and therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 — functional transport assay in transfected cells validated in two additional cell lines with specific inhibitor","pmids":["21633340"],"is_preprint":false},{"year":2012,"finding":"OATP1A2 mRNA expression was most prominently upregulated in LNCaP prostate cancer cells grown under androgen-depleted conditions; DHEAS uptake characteristics in LNCaP cells were consistent with OATP-mediated transport, and siRNA knockdown of OATP1A2 abolished the growth-stimulatory effect of DHEAS, demonstrating a functional role for OATP1A2 in importing DHEAS to support androgen-depleted prostate cancer cell growth.","method":"qRT-PCR; radiolabeled DHEAS uptake assay; siRNA knockdown; cell growth assay","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function siRNA knockdown with defined growth phenotype and functional uptake assay in same study","pmids":["22864060"],"is_preprint":false},{"year":2012,"finding":"The SLCO1A2 gene is transactivated by the vitamin D receptor (VDR): treatment of Caco-2 cells with vitamin D3 increased OATP1A2 mRNA and protein; siRNA knockdown of VDR significantly reduced this induction; a VDR response element (VDRE) in SLCO1A2 promoter variant 1 was confirmed by DNase I footprinting-equivalent in silico prediction, electrophoretic mobility shift assay with recombinant VDR-RXRα, luciferase reporter assays, site-directed mutagenesis abolishing activation, and chromatin immunoprecipitation in living cells.","method":"siRNA knockdown; RT-PCR; Western blotting; luciferase reporter assay; site-directed mutagenesis; EMSA; chromatin immunoprecipitation (ChIP)","journal":"Molecular pharmacology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including mutagenesis, EMSA, ChIP, and functional reporter assays in a single study","pmids":["22474172"],"is_preprint":false},{"year":2013,"finding":"Five novel nonsynonymous SNPs in SLCO1A2 (E184K, D185N, T259P, D288N) were identified and shown to impair estrone-3-sulfate, imatinib, and methotrexate transport (~20–50% of wild-type) in HEK-293 cells; biotinylation assays demonstrated impaired plasma membrane expression for these variants; mutagenesis experiments showed that negative charges at positions 184, 185 support membrane targeting, while bulky substitutions at T259 disrupted transporter stability.","method":"HEK-293 cell transfection; radiolabeled substrate uptake assay; surface biotinylation; site-directed mutagenesis; molecular modeling","journal":"The AAPS journal","confidence":"High","confidence_rationale":"Tier 1-2 — functional transport assay, surface biotinylation, and mutagenesis in a single study with multiple substrates","pmids":["23918469"],"is_preprint":false},{"year":2011,"finding":"OATP1A2 inhibition by naringin (a grapefruit juice component) was identified as a mechanism for grapefruit juice reduction of aliskiren plasma exposure; in vitro, OATP1A2-expressing HEK293 cells showed linear uptake of [14C]aliskiren that was inhibited by naringin (IC50 75.5 µM), while OATP2B1 did not mediate aliskiren transport.","method":"HEK293 transfected cell uptake assay; pharmacological inhibition; human crossover pharmacokinetic study","journal":"European journal of clinical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro mechanistic data corroborated by clinical pharmacokinetic interaction study","pmids":["22124880"],"is_preprint":false},{"year":2014,"finding":"OATP1A2 protein is expressed in retinal photoreceptor bodies and somas of amacrine cells, and in neurons and neuronal processes of human cortex, cerebellum, and hippocampus, as shown by immunofluorescence. Substance P and vasoactive intestinal peptide were identified as substrates for OATP1A2 by transport assay, and double-labeling immunofluorescence showed co-expression of OATP1A2 and substance P in the same retinal neurons, suggesting a role in reuptake of peptide neurotransmitters.","method":"Immunofluorescence localization; double-labeling immunofluorescence; functional transport assay for peptide substrates","journal":"Pflugers Archiv : European journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2-3 — transport substrate identification combined with co-localization immunofluorescence, single study","pmids":["25132355"],"is_preprint":false},{"year":2012,"finding":"Hydrophilic triptans (5-HT1B/1D receptor agonists) are substrates for OATP1A2 as established in a BacMam2-OATP1A2 transduced HEK293 system; kinetics (Km and Vmax) were determined for six marketed triptans. Structure-activity relationship analysis revealed that a positively charged basic amine atom is essential for efficient OATP1A2-mediated triptan uptake; OATP1A2 expressed on the apical side of MDCKII monolayers facilitated apical-to-basolateral transport of triptans.","method":"BacMam2-transduced HEK293 cells; radiolabeled and unlabeled uptake assays; kinetic analysis; SAR with structural analogs; MDCKII polarized transport assay","journal":"Xenobiotica","confidence":"Medium","confidence_rationale":"Tier 2 — kinetic characterization with SAR and directional transport across polarized monolayers","pmids":["22509823"],"is_preprint":false},{"year":2014,"finding":"Liver-specific humanized OATP1A2 transgenic mice showed nearly complete rescue of increased plasma levels of docetaxel observed in Oatp1a/1b-null mice after intravenous administration, demonstrating that OATP1A2 can mediate in vivo hepatic uptake and clearance of docetaxel.","method":"Humanized transgenic mouse model (liver-specific OATP1A2 knockin in Slco1a/1b knockout background); pharmacokinetic analysis; tissue distribution measurement","journal":"International journal of cancer","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic rescue experiment with pharmacokinetic readouts","pmids":["24825069"],"is_preprint":false},{"year":2015,"finding":"All 11 human OATPs including OATP1A2 were functionally expressed in the baculovirus-Sf9 insect cell system; OATP1A2 was shown to transport sodium fluorescein and fluorescein-methotrexate, and OATP1A2 also transported imatinib; acidic extracellular pH greatly facilitated fluorescein uptake by all OATPs.","method":"Baculovirus-Sf9 insect cell expression; fluorescence-based uptake assay; inhibition studies; pH dependency assay","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — functional reconstitution in insect cell expression system with multiple substrates and inhibitors","pmids":["26415544"],"is_preprint":false},{"year":2011,"finding":"OATP1A2 protein is expressed in human placenta and is localized to the vasculo-syncytial membrane (VSM) and apical surface of syncytiotrophoblasts as determined by immunohistochemistry; OATP1A2 mRNA and protein expression were significantly lower in placentas from intrahepatic cholestasis of pregnancy (ICP) compared to normal placentas.","method":"Real-time PCR; Western blotting; immunohistochemistry","journal":"Archives of gynecology and obstetrics","confidence":"Medium","confidence_rationale":"Tier 3 — localization and expression changes without direct functional transport assay in this study","pmids":["22203093"],"is_preprint":false}],"current_model":"OATP1A2 (encoded by SLCO1A2) is a sodium-independent, multispecific organic anion uptake transporter expressed on the luminal membrane of brain capillary endothelial cells (blood-brain barrier), apical membranes of small intestinal enterocytes, renal distal nephron, retinal neurons, and placental syncytiotrophoblasts, where it mediates cellular influx of a broad range of amphipathic substrates including bile salts, steroid conjugates (estrone-3-sulfate, DHEAS), drugs (fexofenadine, saquinavir, imatinib, methotrexate, paclitaxel, docetaxel, triptans, aliskiren), and peptide neurotransmitters (substance P); its expression is transcriptionally upregulated by the vitamin D receptor through a VDRE in the SLCO1A2 promoter, and naturally occurring nonsynonymous SNPs can impair transport by reducing plasma membrane trafficking (with glycosylation and charge-dependent structural effects), while in prostate cancer cells OATP1A2 is upregulated under androgen-depleted conditions to import DHEAS and support cell growth."},"narrative":{"teleology":[{"year":1999,"claim":"Establishing OATP1A2 as a drug uptake transporter: the first demonstration that the previously cloned OATP-A mediates cellular influx of a clinically used drug (fexofenadine), showing it functions as a counterpart to P-glycoprotein-mediated efflux.","evidence":"Recombinant vaccinia expression system with radiolabeled fexofenadine uptake and pharmacological inhibition","pmids":["10421612"],"confidence":"High","gaps":["Substrate specificity beyond fexofenadine was unknown","Tissue-level relevance of OATP1A2-mediated fexofenadine uptake not addressed"]},{"year":2003,"claim":"Broadening substrate scope to endogenous compounds: demonstration that OATP1A2 transports unconjugated bilirubin and identification of its mRNA in liver, placenta, and trophoblast cells extended its potential physiological roles beyond drug transport.","evidence":"Xenopus laevis oocyte expression with radiolabeled bilirubin uptake; RT-PCR in human tissues","pmids":["12568656"],"confidence":"High","gaps":["Bilirubin transport efficiency was very low compared to OATP1B1/1B3, questioning physiological relevance","Placental function of OATP1A2 not directly tested"]},{"year":2004,"claim":"Defining OATP1A2 as an HIV protease inhibitor transporter: reconstitution in Xenopus oocytes showed saturable saquinavir uptake (Km ~36 µM) and competition by known OATP substrates, establishing OATP1A2 in vectorial hepatic drug transport alongside efflux pumps.","evidence":"Xenopus oocyte expression; HepG2 cell uptake with competitive inhibition","pmids":["15832500"],"confidence":"High","gaps":["In vivo contribution of OATP1A2 to saquinavir pharmacokinetics not demonstrated","Relative contribution vs. other OATPs not resolved"]},{"year":2005,"claim":"Linking genetic variants to loss of function and revealing the membrane-trafficking mechanism: naturally occurring SNPs (E172D, N135I) drastically reduced transport of estrone-3-sulfate and opioid peptides by impairing plasma membrane localization, with N135I also altering glycosylation, establishing that surface trafficking is rate-limiting for OATP1A2 activity.","evidence":"Transfected cell transport assays; cell surface biotinylation; confocal microscopy; SDS-PAGE glycosylation analysis; immunohistochemistry in brain and kidney","pmids":["15632119"],"confidence":"High","gaps":["Structural basis for how these mutations disrupt folding/trafficking was not resolved at atomic level","Clinical pharmacogenomic impact of these SNPs was not assessed"]},{"year":2011,"claim":"Expanding the drug substrate portfolio and identifying drug–food interactions: OATP1A2 was shown to transport imatinib, aliskiren, and triptans, with naringin (grapefruit juice component) acting as an OATP1A2 inhibitor explaining reduced oral bioavailability of aliskiren and potentially affecting imatinib uptake.","evidence":"HEK293 transfection uptake assays; pharmacological inhibition with naringin; SAR analysis for triptans; MDCKII polarized monolayer transport; clinical crossover pharmacokinetic study for aliskiren","pmids":["21633340","22124880","22509823"],"confidence":"Medium","gaps":["Relative intestinal contribution of OATP1A2 vs. other uptake/efflux transporters for these drugs not fully delineated","Clinical significance of OATP1A2 genetic variants for triptan or imatinib disposition not tested"]},{"year":2011,"claim":"Placental localization to the syncytiotrophoblast apical membrane was established, and reduced OATP1A2 expression in intrahepatic cholestasis of pregnancy suggested a role in placental bile salt/steroid handling.","evidence":"Immunohistochemistry; Western blotting; real-time PCR in normal vs. ICP placentas","pmids":["22203093"],"confidence":"Medium","gaps":["No direct functional transport assay performed in placental tissue","Causal relationship between OATP1A2 downregulation and ICP pathogenesis not demonstrated"]},{"year":2012,"claim":"Identifying transcriptional regulation by VDR: vitamin D3 treatment upregulated OATP1A2 in Caco-2 cells via a VDRE in the SLCO1A2 promoter, confirmed by EMSA, ChIP, mutagenesis, and reporter assays, establishing a direct transcriptional regulatory mechanism for intestinal OATP1A2 expression.","evidence":"siRNA knockdown of VDR; EMSA with VDR-RXRα; ChIP; luciferase reporter with site-directed mutagenesis; Western blotting","pmids":["22474172"],"confidence":"High","gaps":["Whether VDR regulation operates at the BBB or other OATP1A2-expressing tissues is unknown","Other transcription factors controlling SLCO1A2 expression not identified"]},{"year":2012,"claim":"Functional role in prostate cancer biology: OATP1A2 is upregulated in androgen-depleted prostate cancer cells and mediates DHEAS import that supports cell proliferation, as shown by siRNA knockdown abolishing DHEAS-driven growth.","evidence":"qRT-PCR; radiolabeled DHEAS uptake; siRNA knockdown; cell growth assay in LNCaP cells","pmids":["22864060"],"confidence":"Medium","gaps":["In vivo relevance in castration-resistant prostate cancer not demonstrated","Relative contribution of OATP1A2 vs. other OATP family members in tumor DHEAS uptake unclear"]},{"year":2012,"claim":"In vivo validation via humanized mice: liver-specific OATP1A2 transgenic mice rescued elevated plasma methotrexate and bilirubin in Oatp1a/1b knockouts and uniquely mediated hepatic paclitaxel uptake, providing the first in vivo genetic evidence for OATP1A2 transport function.","evidence":"Humanized transgenic mouse model with pharmacokinetic analysis and tissue distribution","pmids":["23243220"],"confidence":"High","gaps":["Brain and intestinal in vivo contributions of OATP1A2 not addressed by liver-specific transgene","Species differences between mouse and human transport kinetics not fully characterized"]},{"year":2013,"claim":"Deeper pharmacogenomic understanding: five additional SLCO1A2 SNPs were shown to impair transport of multiple substrates by reducing membrane expression, with mutagenesis revealing that negative charges at positions 184/185 support trafficking and bulky substitutions at T259 destabilize the protein.","evidence":"HEK-293 transfection; radiolabeled uptake for estrone-3-sulfate, imatinib, methotrexate; surface biotinylation; site-directed mutagenesis; molecular modeling","pmids":["23918469"],"confidence":"High","gaps":["No high-resolution structure to map variant effects","Population frequencies and clinical pharmacogenomic consequences of these SNPs not established"]},{"year":2014,"claim":"Extending in vivo validation to docetaxel and establishing neuronal roles: OATP1A2 rescued docetaxel clearance in humanized mice; separately, retinal and CNS neuronal expression was demonstrated alongside transport of substance P, suggesting a neurotransmitter reuptake function.","evidence":"Humanized transgenic mouse pharmacokinetics for docetaxel; immunofluorescence double-labeling in retina and brain; functional peptide transport assay","pmids":["24825069","25132355"],"confidence":"High","gaps":["Neurotransmitter reuptake role inferred from co-localization and in vitro transport — no in vivo neuronal function demonstrated","Structural determinants for peptide substrate recognition unknown"]},{"year":null,"claim":"Outstanding questions include the lack of a high-resolution structure, the in vivo physiological importance of OATP1A2 at the blood–brain barrier and in neuronal peptide reuptake, the full spectrum of endogenous substrates, and the clinical pharmacogenomic significance of SLCO1A2 variants across diverse drug classes.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure available","BBB transport function not directly demonstrated in vivo","Endogenous substrate repertoire incompletely defined","Clinical pharmacogenomic impact of variants not established in prospective studies"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1,2,3,4,5,8,9,10,11,12,13]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,8,14]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,1,3,4,5,9,10,11,12,13]},{"term_id":"R-HSA-9748784","term_label":"Drug ADME","supporting_discovery_ids":[0,1,4,5,9,11,12]}],"complexes":[],"partners":["VDR"],"other_free_text":[]},"mechanistic_narrative":"SLCO1A2 encodes OATP1A2, a sodium-independent multispecific organic anion transporter that mediates cellular influx of a structurally diverse array of amphipathic substrates including bile salts, steroid conjugates (estrone-3-sulfate, DHEAS), drugs (fexofenadine, saquinavir, imatinib, methotrexate, paclitaxel, docetaxel, triptans, aliskiren), and peptide neurotransmitters (substance P) [PMID:10421612, PMID:15832500, PMID:23243220, PMID:25132355]. The transporter is expressed at the blood–brain barrier, apical membranes of intestinal enterocytes, renal distal nephron, retinal neurons, and placental syncytiotrophoblasts, where its broad substrate profile supports drug absorption, hepatic clearance, and neurotransmitter reuptake [PMID:15632119, PMID:25132355, PMID:22203093, PMID:24825069]. Transcription of SLCO1A2 is upregulated by the vitamin D receptor through a VDRE in the promoter, and under androgen-depleted conditions in prostate cancer cells OATP1A2 imports DHEAS to sustain cell growth [PMID:22474172, PMID:22864060]. Naturally occurring nonsynonymous variants impair transport function by reducing plasma membrane trafficking through mechanisms involving altered glycosylation and charge-dependent structural destabilization [PMID:15632119, PMID:23918469]."},"prefetch_data":{"uniprot":{"accession":"P46721","full_name":"Solute carrier organic anion transporter family member 1A2","aliases":["OATP-A","Organic anion-transporting polypeptide 1","OATP-1","Sodium-independent organic anion transporter","Solute carrier family 21 member 3"],"length_aa":670,"mass_kda":74.1,"function":"Na(+)-independent transporter that mediates the cellular uptake of a broad range of organic anions such as the endogenous bile salts cholate and deoxycholate, either in their unconjugated or conjugated forms (taurocholate and glycocholate), at the plasmam membrane (PubMed:19129463, PubMed:7557095). Responsible for intestinal absorption of bile acids (By similarity). Transports dehydroepiandrosterone 3-sulfate (DHEAS), a major circulating steroid secreted by the adrenal cortex, as well as estrone 3-sulfate and 17beta-estradiol 17-O-(beta-D-glucuronate) (PubMed:11159893, PubMed:12568656, PubMed:19129463, PubMed:23918469, PubMed:25560245, PubMed:9539145). Mediates apical uptake of all-trans-retinol (atROL) across human retinal pigment epithelium, which is essential to maintaining the integrity of the visual cycle and thus vision (PubMed:25560245). Involved in the uptake of clinically used drugs (PubMed:17301733, PubMed:20686826, PubMed:27777271). Capable of thyroid hormone transport (both T3 or 3,3',5'-triiodo-L-thyronine, and T4 or L-tyroxine) (PubMed:19129463, PubMed:20358049). Also transports prostaglandin E2 (PubMed:19129463). Plays roles in blood-brain and -cerebrospinal fluid barrier transport of organic anions and signal mediators, and in hormone uptake by neural cells (By similarity). May also play a role in the reuptake of neuropeptides such as substance P/TAC1 and vasoactive intestinal peptide/VIP released from retinal neurons (PubMed:25132355). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drugs methotrexate and paclitaxel (PubMed:23243220). Shows a pH-sensitive substrate specificity which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463). May contribute to regulate the transport of organic compounds in testis across the blood-testis-barrier (Probable)","subcellular_location":"Cell membrane; Basal cell membrane","url":"https://www.uniprot.org/uniprotkb/P46721/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLCO1A2","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SLCO1A2","total_profiled":1310},"omim":[{"mim_id":"613389","title":"SOLUTE CARRIER ORGANIC ANION TRANSPORTER FAMILY, MEMBER 1C1; SLCO1C1","url":"https://www.omim.org/entry/613389"},{"mim_id":"612436","title":"SOLUTE CARRIER ORGANIC ANION TRANSPORTER FAMILY, MEMBER 4A1; SLCO4A1","url":"https://www.omim.org/entry/612436"},{"mim_id":"612435","title":"SOLUTE CARRIER ORGANIC ANION TRANSPORTER FAMILY, MEMBER 3A1; SLCO3A1","url":"https://www.omim.org/entry/612435"},{"mim_id":"605495","title":"SOLUTE CARRIER ORGANIC ANION TRANSPORTER FAMILY, MEMBER 1B3; SLCO1B3","url":"https://www.omim.org/entry/605495"},{"mim_id":"604988","title":"SOLUTE CARRIER ORGANIC ANION TRANSPORTER FAMILY, MEMBER 2B1; SLCO2B1","url":"https://www.omim.org/entry/604988"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":15.0},{"tissue":"choroid plexus","ntpm":7.0},{"tissue":"liver","ntpm":7.5},{"tissue":"salivary gland","ntpm":14.6}],"url":"https://www.proteinatlas.org/search/SLCO1A2"},"hgnc":{"alias_symbol":["OATP","OATP1A2","OATP-A"],"prev_symbol":["SLC21A3"]},"alphafold":{"accession":"P46721","domains":[{"cath_id":"-","chopping":"414-501","consensus_level":"medium","plddt":84.0807,"start":414,"end":501}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P46721","model_url":"https://alphafold.ebi.ac.uk/files/AF-P46721-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P46721-F1-predicted_aligned_error_v6.png","plddt_mean":80.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLCO1A2","jax_strain_url":"https://www.jax.org/strain/search?query=SLCO1A2"},"sequence":{"accession":"P46721","fasta_url":"https://rest.uniprot.org/uniprotkb/P46721.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P46721/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P46721"}},"corpus_meta":[{"pmid":"19785645","id":"PMC_19785645","title":"Impact of OATP 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of the CNS","url":"https://pubmed.ncbi.nlm.nih.gov/24083450","citation_count":36,"is_preprint":false},{"pmid":"15519273","id":"PMC_15519273","title":"Influence of common variants in the pharmacokinetic genes (OATP-C, UGT1A1, and MRP2) on serum bilirubin levels in healthy subjects.","date":"2004","source":"Hepatology research : the official journal of the Japan Society of Hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/15519273","citation_count":36,"is_preprint":false},{"pmid":"24643910","id":"PMC_24643910","title":"Role of OATP-1B1 and/or OATP-1B3 in hepatic disposition of tyrosine kinase inhibitors.","date":"2014","source":"Drug metabolism and drug interactions","url":"https://pubmed.ncbi.nlm.nih.gov/24643910","citation_count":35,"is_preprint":false},{"pmid":"31093828","id":"PMC_31093828","title":"Characterization of Plasma Membrane Localization and Phosphorylation Status of Organic Anion Transporting Polypeptide (OATP) 1B1 c.521 T>C Nonsynonymous Single-Nucleotide Polymorphism.","date":"2019","source":"Pharmaceutical research","url":"https://pubmed.ncbi.nlm.nih.gov/31093828","citation_count":35,"is_preprint":false},{"pmid":"22509823","id":"PMC_22509823","title":"Hydrophilic anti-migraine triptans are substrates for OATP1A2, a transporter expressed at human blood-brain barrier.","date":"2012","source":"Xenobiotica; the fate of foreign compounds in biological systems","url":"https://pubmed.ncbi.nlm.nih.gov/22509823","citation_count":34,"is_preprint":false},{"pmid":"29732104","id":"PMC_29732104","title":"Dual-channel fluorescence diagnosis of cancer cells/tissues assisted by OATP transporters and cysteine/glutathione.","date":"2018","source":"Chemical science","url":"https://pubmed.ncbi.nlm.nih.gov/29732104","citation_count":32,"is_preprint":false},{"pmid":"20176623","id":"PMC_20176623","title":"Mechanism of polybrominated diphenyl ether uptake into the liver: PBDE congeners are substrates of human hepatic OATP transporters.","date":"2010","source":"Toxicological sciences : an official journal of the Society of Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/20176623","citation_count":32,"is_preprint":false},{"pmid":"22203093","id":"PMC_22203093","title":"Alteration in placental expression of bile acids transporters OATP1A2, OATP1B1, OATP1B3 in intrahepatic cholestasis of pregnancy.","date":"2011","source":"Archives of gynecology and obstetrics","url":"https://pubmed.ncbi.nlm.nih.gov/22203093","citation_count":31,"is_preprint":false},{"pmid":"26055554","id":"PMC_26055554","title":"Zebrafish Oatp-mediated transport of microcystin congeners.","date":"2015","source":"Archives of toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/26055554","citation_count":31,"is_preprint":false},{"pmid":"29746136","id":"PMC_29746136","title":"Relative Activity Factor (RAF)-Based Scaling of Uptake Clearance Mediated by Organic Anion Transporting Polypeptide (OATP) 1B1 and OATP1B3 in Human Hepatocytes.","date":"2018","source":"Molecular pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/29746136","citation_count":31,"is_preprint":false},{"pmid":"19628752","id":"PMC_19628752","title":"Construction of triple-transfected cells [organic anion-transporting polypeptide (OATP) 1B1/multidrug resistance-associated protein (MRP) 2/MRP3 and OATP1B1/MRP2/MRP4] for analysis of the sinusoidal function of MRP3 and MRP4.","date":"2009","source":"Drug metabolism and disposition: the biological fate of chemicals","url":"https://pubmed.ncbi.nlm.nih.gov/19628752","citation_count":31,"is_preprint":false},{"pmid":"17174077","id":"PMC_17174077","title":"Evidence of Oatp and Mdr1 in cryopreserved rat hepatocytes.","date":"2006","source":"European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/17174077","citation_count":30,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":57529,"output_tokens":4177,"usd":0.117621},"stage2":{"model":"claude-opus-4-6","input_tokens":7590,"output_tokens":3146,"usd":0.1749},"total_usd":0.292521,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"Human OATP1A2 (OATP-A) mediates cellular uptake of fexofenadine, as demonstrated using a recombinant vaccinia expression system; P-glycoprotein was identified as the efflux transporter for the same drug, and several P-gp inhibitors also inhibited OATP.\",\n      \"method\": \"Recombinant vaccinia expression system in cells; radiolabeled substrate uptake assay\",\n      \"journal\": \"Drug metabolism and disposition\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted transport activity in recombinant expression system with pharmacological inhibition controls\",\n      \"pmids\": [\"10421612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"OATP1A2 (OATP-A/SLC21A3) mediates influx transport of saquinavir (HIV protease inhibitor) in Xenopus laevis oocytes injected with OATP-A cRNA, with saturable kinetics (Km = 36.4 µM); in HepG2 hepatic cells, OATP-A substrates competitively inhibited saquinavir uptake, indicating OATP-A acts in concert with apical P-gp and MRP2 for vectorial hepatic transport.\",\n      \"method\": \"Xenopus laevis oocyte expression system; HepG2 cell uptake assays with pharmacological inhibitors; saturation kinetics\",\n      \"journal\": \"Molecular pharmaceutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in Xenopus oocytes plus functional validation in hepatic cells with multiple inhibitors\",\n      \"pmids\": [\"15832500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"OATP1A2 is expressed in human brain capillary endothelial cells and renal distal nephron as demonstrated by immunohistochemistry. Naturally occurring nonsynonymous SNPs in SLCO1A2 (A516C/E172D and A404T/N135I) markedly reduced transport of estrone 3-sulfate, deltorphin II, and DPDPE; reduced plasma membrane expression contributed to loss of function as shown by cell surface biotinylation and confocal microscopy. The A404T variant also showed altered glycosylation.\",\n      \"method\": \"Immunohistochemistry; in vitro transport assays in transfected cells; cell surface biotinylation; immunofluorescence confocal microscopy; SDS-PAGE for glycosylation analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including functional transport assay, surface biotinylation, microscopy, and glycosylation analysis in a single study\",\n      \"pmids\": [\"15632119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"OATP1A2 (OATP-A) mRNA was identified in human liver, placenta, and purified trophoblast cells by RT-PCR and sequencing; injection of OATP-A mRNA into Xenopus laevis oocytes conferred ability to take up unconjugated bilirubin (UCB), though with very low efficiency compared to OATP-8 and OATP-C.\",\n      \"method\": \"RT-PCR/sequencing; real-time quantitative RT-PCR; Xenopus laevis oocyte expression with radiolabeled substrate uptake and kinetic analysis\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted transport function in Xenopus oocytes with kinetic analysis\",\n      \"pmids\": [\"12568656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Liver-specific humanized OATP1A2 transgenic mice showed partial rescue of increased plasma bilirubin and increased plasma levels of methotrexate seen in Slco1a/1b knockout mice; OATP1A2 (but not OATP1B1) significantly increased liver uptake of paclitaxel (2 mg/kg), demonstrating in vivo transport function of OATP1A2 for both organic anionic (methotrexate) and hydrophobic bulky (paclitaxel) substrates.\",\n      \"method\": \"Humanized transgenic mouse model (liver-specific OATP1A2 knockin in Slco1a/1b knockout background); pharmacokinetic analysis; tissue distribution measurement\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic rescue experiment with pharmacokinetic readouts replicated across multiple substrate drugs\",\n      \"pmids\": [\"23243220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Imatinib uptake was significantly enhanced in OATP1A2-transfected HEK293 cells; naringin (an OATP1A2 inhibitor) decreased imatinib transport in OATP1A2-transfected HEK293 cells, human intestinal Caco-2 cells, and K562 CML cells, establishing OATP1A2 as a transporter of imatinib into cells.\",\n      \"method\": \"HEK293 transfection uptake assay; pharmacological inhibition with naringin in multiple cell lines\",\n      \"journal\": \"Clinical pharmacology and therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional transport assay in transfected cells validated in two additional cell lines with specific inhibitor\",\n      \"pmids\": [\"21633340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"OATP1A2 mRNA expression was most prominently upregulated in LNCaP prostate cancer cells grown under androgen-depleted conditions; DHEAS uptake characteristics in LNCaP cells were consistent with OATP-mediated transport, and siRNA knockdown of OATP1A2 abolished the growth-stimulatory effect of DHEAS, demonstrating a functional role for OATP1A2 in importing DHEAS to support androgen-depleted prostate cancer cell growth.\",\n      \"method\": \"qRT-PCR; radiolabeled DHEAS uptake assay; siRNA knockdown; cell growth assay\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function siRNA knockdown with defined growth phenotype and functional uptake assay in same study\",\n      \"pmids\": [\"22864060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The SLCO1A2 gene is transactivated by the vitamin D receptor (VDR): treatment of Caco-2 cells with vitamin D3 increased OATP1A2 mRNA and protein; siRNA knockdown of VDR significantly reduced this induction; a VDR response element (VDRE) in SLCO1A2 promoter variant 1 was confirmed by DNase I footprinting-equivalent in silico prediction, electrophoretic mobility shift assay with recombinant VDR-RXRα, luciferase reporter assays, site-directed mutagenesis abolishing activation, and chromatin immunoprecipitation in living cells.\",\n      \"method\": \"siRNA knockdown; RT-PCR; Western blotting; luciferase reporter assay; site-directed mutagenesis; EMSA; chromatin immunoprecipitation (ChIP)\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including mutagenesis, EMSA, ChIP, and functional reporter assays in a single study\",\n      \"pmids\": [\"22474172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Five novel nonsynonymous SNPs in SLCO1A2 (E184K, D185N, T259P, D288N) were identified and shown to impair estrone-3-sulfate, imatinib, and methotrexate transport (~20–50% of wild-type) in HEK-293 cells; biotinylation assays demonstrated impaired plasma membrane expression for these variants; mutagenesis experiments showed that negative charges at positions 184, 185 support membrane targeting, while bulky substitutions at T259 disrupted transporter stability.\",\n      \"method\": \"HEK-293 cell transfection; radiolabeled substrate uptake assay; surface biotinylation; site-directed mutagenesis; molecular modeling\",\n      \"journal\": \"The AAPS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — functional transport assay, surface biotinylation, and mutagenesis in a single study with multiple substrates\",\n      \"pmids\": [\"23918469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"OATP1A2 inhibition by naringin (a grapefruit juice component) was identified as a mechanism for grapefruit juice reduction of aliskiren plasma exposure; in vitro, OATP1A2-expressing HEK293 cells showed linear uptake of [14C]aliskiren that was inhibited by naringin (IC50 75.5 µM), while OATP2B1 did not mediate aliskiren transport.\",\n      \"method\": \"HEK293 transfected cell uptake assay; pharmacological inhibition; human crossover pharmacokinetic study\",\n      \"journal\": \"European journal of clinical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro mechanistic data corroborated by clinical pharmacokinetic interaction study\",\n      \"pmids\": [\"22124880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"OATP1A2 protein is expressed in retinal photoreceptor bodies and somas of amacrine cells, and in neurons and neuronal processes of human cortex, cerebellum, and hippocampus, as shown by immunofluorescence. Substance P and vasoactive intestinal peptide were identified as substrates for OATP1A2 by transport assay, and double-labeling immunofluorescence showed co-expression of OATP1A2 and substance P in the same retinal neurons, suggesting a role in reuptake of peptide neurotransmitters.\",\n      \"method\": \"Immunofluorescence localization; double-labeling immunofluorescence; functional transport assay for peptide substrates\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — transport substrate identification combined with co-localization immunofluorescence, single study\",\n      \"pmids\": [\"25132355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Hydrophilic triptans (5-HT1B/1D receptor agonists) are substrates for OATP1A2 as established in a BacMam2-OATP1A2 transduced HEK293 system; kinetics (Km and Vmax) were determined for six marketed triptans. Structure-activity relationship analysis revealed that a positively charged basic amine atom is essential for efficient OATP1A2-mediated triptan uptake; OATP1A2 expressed on the apical side of MDCKII monolayers facilitated apical-to-basolateral transport of triptans.\",\n      \"method\": \"BacMam2-transduced HEK293 cells; radiolabeled and unlabeled uptake assays; kinetic analysis; SAR with structural analogs; MDCKII polarized transport assay\",\n      \"journal\": \"Xenobiotica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — kinetic characterization with SAR and directional transport across polarized monolayers\",\n      \"pmids\": [\"22509823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Liver-specific humanized OATP1A2 transgenic mice showed nearly complete rescue of increased plasma levels of docetaxel observed in Oatp1a/1b-null mice after intravenous administration, demonstrating that OATP1A2 can mediate in vivo hepatic uptake and clearance of docetaxel.\",\n      \"method\": \"Humanized transgenic mouse model (liver-specific OATP1A2 knockin in Slco1a/1b knockout background); pharmacokinetic analysis; tissue distribution measurement\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic rescue experiment with pharmacokinetic readouts\",\n      \"pmids\": [\"24825069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"All 11 human OATPs including OATP1A2 were functionally expressed in the baculovirus-Sf9 insect cell system; OATP1A2 was shown to transport sodium fluorescein and fluorescein-methotrexate, and OATP1A2 also transported imatinib; acidic extracellular pH greatly facilitated fluorescein uptake by all OATPs.\",\n      \"method\": \"Baculovirus-Sf9 insect cell expression; fluorescence-based uptake assay; inhibition studies; pH dependency assay\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional reconstitution in insect cell expression system with multiple substrates and inhibitors\",\n      \"pmids\": [\"26415544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"OATP1A2 protein is expressed in human placenta and is localized to the vasculo-syncytial membrane (VSM) and apical surface of syncytiotrophoblasts as determined by immunohistochemistry; OATP1A2 mRNA and protein expression were significantly lower in placentas from intrahepatic cholestasis of pregnancy (ICP) compared to normal placentas.\",\n      \"method\": \"Real-time PCR; Western blotting; immunohistochemistry\",\n      \"journal\": \"Archives of gynecology and obstetrics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — localization and expression changes without direct functional transport assay in this study\",\n      \"pmids\": [\"22203093\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"OATP1A2 (encoded by SLCO1A2) is a sodium-independent, multispecific organic anion uptake transporter expressed on the luminal membrane of brain capillary endothelial cells (blood-brain barrier), apical membranes of small intestinal enterocytes, renal distal nephron, retinal neurons, and placental syncytiotrophoblasts, where it mediates cellular influx of a broad range of amphipathic substrates including bile salts, steroid conjugates (estrone-3-sulfate, DHEAS), drugs (fexofenadine, saquinavir, imatinib, methotrexate, paclitaxel, docetaxel, triptans, aliskiren), and peptide neurotransmitters (substance P); its expression is transcriptionally upregulated by the vitamin D receptor through a VDRE in the SLCO1A2 promoter, and naturally occurring nonsynonymous SNPs can impair transport by reducing plasma membrane trafficking (with glycosylation and charge-dependent structural effects), while in prostate cancer cells OATP1A2 is upregulated under androgen-depleted conditions to import DHEAS and support cell growth.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SLCO1A2 encodes OATP1A2, a sodium-independent multispecific organic anion transporter that mediates cellular influx of a structurally diverse array of amphipathic substrates including bile salts, steroid conjugates (estrone-3-sulfate, DHEAS), drugs (fexofenadine, saquinavir, imatinib, methotrexate, paclitaxel, docetaxel, triptans, aliskiren), and peptide neurotransmitters (substance P) [PMID:10421612, PMID:15832500, PMID:23243220, PMID:25132355]. The transporter is expressed at the blood–brain barrier, apical membranes of intestinal enterocytes, renal distal nephron, retinal neurons, and placental syncytiotrophoblasts, where its broad substrate profile supports drug absorption, hepatic clearance, and neurotransmitter reuptake [PMID:15632119, PMID:25132355, PMID:22203093, PMID:24825069]. Transcription of SLCO1A2 is upregulated by the vitamin D receptor through a VDRE in the promoter, and under androgen-depleted conditions in prostate cancer cells OATP1A2 imports DHEAS to sustain cell growth [PMID:22474172, PMID:22864060]. Naturally occurring nonsynonymous variants impair transport function by reducing plasma membrane trafficking through mechanisms involving altered glycosylation and charge-dependent structural destabilization [PMID:15632119, PMID:23918469].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing OATP1A2 as a drug uptake transporter: the first demonstration that the previously cloned OATP-A mediates cellular influx of a clinically used drug (fexofenadine), showing it functions as a counterpart to P-glycoprotein-mediated efflux.\",\n      \"evidence\": \"Recombinant vaccinia expression system with radiolabeled fexofenadine uptake and pharmacological inhibition\",\n      \"pmids\": [\"10421612\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate specificity beyond fexofenadine was unknown\", \"Tissue-level relevance of OATP1A2-mediated fexofenadine uptake not addressed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Broadening substrate scope to endogenous compounds: demonstration that OATP1A2 transports unconjugated bilirubin and identification of its mRNA in liver, placenta, and trophoblast cells extended its potential physiological roles beyond drug transport.\",\n      \"evidence\": \"Xenopus laevis oocyte expression with radiolabeled bilirubin uptake; RT-PCR in human tissues\",\n      \"pmids\": [\"12568656\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Bilirubin transport efficiency was very low compared to OATP1B1/1B3, questioning physiological relevance\", \"Placental function of OATP1A2 not directly tested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defining OATP1A2 as an HIV protease inhibitor transporter: reconstitution in Xenopus oocytes showed saturable saquinavir uptake (Km ~36 µM) and competition by known OATP substrates, establishing OATP1A2 in vectorial hepatic drug transport alongside efflux pumps.\",\n      \"evidence\": \"Xenopus oocyte expression; HepG2 cell uptake with competitive inhibition\",\n      \"pmids\": [\"15832500\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo contribution of OATP1A2 to saquinavir pharmacokinetics not demonstrated\", \"Relative contribution vs. other OATPs not resolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Linking genetic variants to loss of function and revealing the membrane-trafficking mechanism: naturally occurring SNPs (E172D, N135I) drastically reduced transport of estrone-3-sulfate and opioid peptides by impairing plasma membrane localization, with N135I also altering glycosylation, establishing that surface trafficking is rate-limiting for OATP1A2 activity.\",\n      \"evidence\": \"Transfected cell transport assays; cell surface biotinylation; confocal microscopy; SDS-PAGE glycosylation analysis; immunohistochemistry in brain and kidney\",\n      \"pmids\": [\"15632119\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for how these mutations disrupt folding/trafficking was not resolved at atomic level\", \"Clinical pharmacogenomic impact of these SNPs was not assessed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Expanding the drug substrate portfolio and identifying drug–food interactions: OATP1A2 was shown to transport imatinib, aliskiren, and triptans, with naringin (grapefruit juice component) acting as an OATP1A2 inhibitor explaining reduced oral bioavailability of aliskiren and potentially affecting imatinib uptake.\",\n      \"evidence\": \"HEK293 transfection uptake assays; pharmacological inhibition with naringin; SAR analysis for triptans; MDCKII polarized monolayer transport; clinical crossover pharmacokinetic study for aliskiren\",\n      \"pmids\": [\"21633340\", \"22124880\", \"22509823\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative intestinal contribution of OATP1A2 vs. other uptake/efflux transporters for these drugs not fully delineated\", \"Clinical significance of OATP1A2 genetic variants for triptan or imatinib disposition not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Placental localization to the syncytiotrophoblast apical membrane was established, and reduced OATP1A2 expression in intrahepatic cholestasis of pregnancy suggested a role in placental bile salt/steroid handling.\",\n      \"evidence\": \"Immunohistochemistry; Western blotting; real-time PCR in normal vs. ICP placentas\",\n      \"pmids\": [\"22203093\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct functional transport assay performed in placental tissue\", \"Causal relationship between OATP1A2 downregulation and ICP pathogenesis not demonstrated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identifying transcriptional regulation by VDR: vitamin D3 treatment upregulated OATP1A2 in Caco-2 cells via a VDRE in the SLCO1A2 promoter, confirmed by EMSA, ChIP, mutagenesis, and reporter assays, establishing a direct transcriptional regulatory mechanism for intestinal OATP1A2 expression.\",\n      \"evidence\": \"siRNA knockdown of VDR; EMSA with VDR-RXRα; ChIP; luciferase reporter with site-directed mutagenesis; Western blotting\",\n      \"pmids\": [\"22474172\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether VDR regulation operates at the BBB or other OATP1A2-expressing tissues is unknown\", \"Other transcription factors controlling SLCO1A2 expression not identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Functional role in prostate cancer biology: OATP1A2 is upregulated in androgen-depleted prostate cancer cells and mediates DHEAS import that supports cell proliferation, as shown by siRNA knockdown abolishing DHEAS-driven growth.\",\n      \"evidence\": \"qRT-PCR; radiolabeled DHEAS uptake; siRNA knockdown; cell growth assay in LNCaP cells\",\n      \"pmids\": [\"22864060\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance in castration-resistant prostate cancer not demonstrated\", \"Relative contribution of OATP1A2 vs. other OATP family members in tumor DHEAS uptake unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"In vivo validation via humanized mice: liver-specific OATP1A2 transgenic mice rescued elevated plasma methotrexate and bilirubin in Oatp1a/1b knockouts and uniquely mediated hepatic paclitaxel uptake, providing the first in vivo genetic evidence for OATP1A2 transport function.\",\n      \"evidence\": \"Humanized transgenic mouse model with pharmacokinetic analysis and tissue distribution\",\n      \"pmids\": [\"23243220\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Brain and intestinal in vivo contributions of OATP1A2 not addressed by liver-specific transgene\", \"Species differences between mouse and human transport kinetics not fully characterized\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Deeper pharmacogenomic understanding: five additional SLCO1A2 SNPs were shown to impair transport of multiple substrates by reducing membrane expression, with mutagenesis revealing that negative charges at positions 184/185 support trafficking and bulky substitutions at T259 destabilize the protein.\",\n      \"evidence\": \"HEK-293 transfection; radiolabeled uptake for estrone-3-sulfate, imatinib, methotrexate; surface biotinylation; site-directed mutagenesis; molecular modeling\",\n      \"pmids\": [\"23918469\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure to map variant effects\", \"Population frequencies and clinical pharmacogenomic consequences of these SNPs not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extending in vivo validation to docetaxel and establishing neuronal roles: OATP1A2 rescued docetaxel clearance in humanized mice; separately, retinal and CNS neuronal expression was demonstrated alongside transport of substance P, suggesting a neurotransmitter reuptake function.\",\n      \"evidence\": \"Humanized transgenic mouse pharmacokinetics for docetaxel; immunofluorescence double-labeling in retina and brain; functional peptide transport assay\",\n      \"pmids\": [\"24825069\", \"25132355\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Neurotransmitter reuptake role inferred from co-localization and in vitro transport — no in vivo neuronal function demonstrated\", \"Structural determinants for peptide substrate recognition unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Outstanding questions include the lack of a high-resolution structure, the in vivo physiological importance of OATP1A2 at the blood–brain barrier and in neuronal peptide reuptake, the full spectrum of endogenous substrates, and the clinical pharmacogenomic significance of SLCO1A2 variants across diverse drug classes.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal or cryo-EM structure available\", \"BBB transport function not directly demonstrated in vivo\", \"Endogenous substrate repertoire incompletely defined\", \"Clinical pharmacogenomic impact of variants not established in prospective studies\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 5, 8, 9, 10, 11, 12, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 8, 14]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": []}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 1, 3, 4, 5, 9, 10, 11, 12, 13]},\n      {\"term_id\": \"R-HSA-9748784\", \"supporting_discovery_ids\": [0, 1, 4, 5, 9, 11, 12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"VDR\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}