{"gene":"SLCO1B3","run_date":"2026-06-10T07:46:35","timeline":{"discoveries":[{"year":2001,"finding":"OATP1B3 (SLC21A8/OATP8) mediates basolateral uptake of organic anions (BSP, leukotriene C4, 17β-glucuronosyl estradiol, DHEA-S, fluo-3, rifampicin) in hepatocytes; vectorial transcellular transport from basolateral to apical compartment was reconstituted in double-transfected MDCK cells co-expressing OATP1B3 at the basolateral membrane and ABCC2/MRP2 at the apical membrane, demonstrating cooperative hepatobiliary elimination.","method":"Double-transfected MDCK cell Transwell transport assay; immunoblotting; confocal laser scanning microscopy for protein localization","journal":"Molecular pharmacology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted vectorial transport in a defined double-transfected cell system with multiple substrates, immunofluorescence localization, and direct transport measurement","pmids":["11641421"],"is_preprint":false},{"year":2003,"finding":"OATP1B3 (SLC21A8/OATP8) is localized to the basolateral (sinusoidal) membrane of human hepatocytes; both OATP1B3 and OATP1B1 were detected in hepatocellular carcinoma with irregular staining pattern but absent in HepG2 cells and absent in cholangiocarcinoma/colorectal/pancreatic liver metastases.","method":"Immunoblot, immunoprecipitation, immunofluorescence microscopy with monoclonal antibodies; immunohistochemistry on paraffin sections of liver tumors","journal":"Laboratory investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by immunofluorescence and IHC with characterized antibodies, single lab, multiple methods","pmids":["12695556"],"is_preprint":false},{"year":2003,"finding":"OATP1B3 (OATP-8) transports unconjugated bilirubin (UCB) and 17β-glucuronosyl estradiol in a carrier-mediated, saturable manner when expressed in Xenopus laevis oocytes; OATP1B3 mRNA is expressed in human placental trophoblasts suggesting a role in fetal UCB clearance via the placenta-maternal liver tandem.","method":"Xenopus oocyte expression system; radiolabeled substrate uptake assay; RT-PCR and real-time quantitative RT-PCR; kinetic analysis","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro transport reconstitution in oocytes with kinetics, single lab","pmids":["12568656"],"is_preprint":false},{"year":2004,"finding":"OATP1B3 mediates Na+-independent, saturable uptake of pitavastatin (Km ~3.3 µM) in HEK293 cells; OATP1B1 accounts for ~90% of total hepatic uptake of pitavastatin in humans based on relative activity factor methodology.","method":"Transporter-expressing HEK293 cells; radiolabeled uptake assay; Western blot for relative expression; cryopreserved human hepatocyte uptake assay","journal":"The Journal of pharmacology and experimental therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — uptake kinetics in transfected cells plus human hepatocyte validation, single lab, two orthogonal methods","pmids":["15159445"],"is_preprint":false},{"year":2004,"finding":"Mutations in SLCO1B3 have substrate-specific functional consequences: OATP1B3-G522C and OATP1B3-G583E (rare/artificial mutations) are retained intracellularly and abolish bile acid transport but retain transport of BSP; common polymorphisms S112A and M233I show normal lateral membrane localization and comparable transport activity.","method":"Site-directed mutagenesis; stable transfection in MDCKII and HEK293 cells; immunofluorescence for localization; radiolabeled substrate transport assays","journal":"Pharmacogenetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis combined with localization and functional transport assays in two cell systems, rigorous controls","pmids":["15226676"],"is_preprint":false},{"year":2004,"finding":"HNF3β (FOXA2) transcriptionally represses the SLCO1B3 (OATP8) gene promoter; an HNF3β binding site was mapped to nucleotides -39/-23 of the OATP8 promoter by EMSA; HNF3β cotransfection reduced OATP8 promoter activity by ~70% in Huh7 cells and inversely correlated with OATP8 mRNA/protein in HCC.","method":"Luciferase reporter assay; electrophoretic mobility shift assay (EMSA); real-time PCR; Western blot; correlation analysis in 13 paired HCC/non-tumor liver samples","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — EMSA binding site mapping plus functional reporter assay plus clinical correlation, single lab, multiple orthogonal methods","pmids":["14739090"],"is_preprint":false},{"year":2005,"finding":"OATP1B3 mediates high-affinity, saturable uptake of the peptide CCK-8 (cholecystokinin-8) at the basolateral membrane; vectorial transport of CCK-8 across MDCK cells requires both OATP1B3 (uptake) and ABCC2/MRP2 (apical efflux); MRP2 transports CCK-8 with Km = 8.1 µM in an ATP-dependent manner; cyclosporin A inhibits OATP1B3 uptake (Ki = 1.2 µM).","method":"Double-transfected MDCKII Transwell vectorial transport assay; membrane vesicle ATP-dependent transport assay; immunofluorescence microscopy; radiolabeled substrate uptake","journal":"The Journal of pharmacology and experimental therapeutics","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted vectorial transport in defined double-transfected system, ATP-dependent vesicle assay for MRP2, kinetic parameters determined, rigorous controls","pmids":["15665139"],"is_preprint":false},{"year":2006,"finding":"OATP1B3 is the predominant transporter for hepatic uptake of telmisartan (Km = 0.81 µM) in humans; OATP1B1-expressing cells showed no significant uptake; selective inhibition with estrone-3-sulfate in human hepatocytes confirmed OATP1B3 predominance.","method":"HEK293 cells stably expressing OATP1B1 or OATP1B3; cryopreserved human hepatocyte uptake assay; selective inhibition studies; kinetic analysis","journal":"Drug metabolism and disposition","confidence":"High","confidence_rationale":"Tier 2 / Strong — uptake kinetics in transfected cells confirmed in human hepatocytes with selective inhibitor, multiple orthogonal methods, replicated across systems","pmids":["16611857"],"is_preprint":false},{"year":2006,"finding":"OATP1B3 mediates Na+-independent, saturable uptake of olmesartan (Km = 71.8 µM) in Xenopus oocytes; OATP1B1 also transports olmesartan (Km = 42.6 µM); biliary excretion is mediated by MRP2 as shown by drastically reduced cumulative biliary excretion in EHBR (mrp2-deficient) rats.","method":"Xenopus oocyte expression; radiolabeled transport assay; EHBR rat in vivo model; canalicular membrane vesicle ATP-dependent transport assay; MRP2-expressing vesicles","journal":"Drug metabolism and disposition","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — oocyte transport assay plus in vivo EHBR rat model plus vesicle assay, single lab, multiple orthogonal methods","pmids":["16501004"],"is_preprint":false},{"year":2006,"finding":"OATP1B3 transports TUDC and GUDC (bile acid conjugates) but not unconjugated UDCA in HEK293 expression systems; NTCP also transports UDCA and its conjugates; differential Na+-dependent and -independent contributions to hepatic uptake of UDCA conjugates were established.","method":"Transporter-expressing HEK293 cells; radiolabeled substrate uptake assay; Na+ replacement experiments; cryopreserved human hepatocyte uptake assays","journal":"Molecular pharmaceutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — uptake assays in transfected cells validated in human hepatocytes, single lab, two orthogonal systems","pmids":["16686371"],"is_preprint":false},{"year":2006,"finding":"OATP1B3 (OATP8/1B3) can mediate bile acid efflux in a glutathione-dependent manner: GSH cis-stimulates OATP1B3-mediated bile acid transport and is itself co-transported with a stoichiometry of 2:1 (GSH:bile acid); this cotransport was not observed for OATP1B1, suggesting OATP1B3 may function as a bidirectional transporter acting as a basolateral organic anion export route.","method":"Xenopus oocyte expression system with cholic acid methyl ester loading; radiolabeled trans-activation/inhibition assays; kinetic analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution in oocytes with kinetic analysis of cotransport stoichiometry, single lab","pmids":["16877380"],"is_preprint":false},{"year":2007,"finding":"Bosentan and its metabolite Ro 48-5033 are substrates of OATP1B3; cyclosporin A and rifampicin inhibit OATP1B3-mediated bosentan uptake with IC50 values below effective plasma concentrations; sildenafil also inhibits OATP1B3-mediated transport at supratherapeutic concentrations, establishing inhibition of hepatic uptake as the mechanism of drug-drug interactions.","method":"CHO cells stably expressing OATP1B1 and OATP1B3; radiolabeled uptake assay; IC50 determination; comparison with clinical plasma concentrations","journal":"Drug metabolism and disposition","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transport assays in transfected cells with IC50 determination, single lab, mechanistic DDI interpretation","pmids":["17496208"],"is_preprint":false},{"year":2007,"finding":"OATP1B3 is the only human OATP capable of transporting paclitaxel to a significant extent among OATP1A2, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, and NTCP tested; common SNPs 334T>G and 699G>A in SLCO1B3 were not associated with paclitaxel pharmacokinetics in European patients.","method":"Xenopus laevis oocyte cRNA injection; radiolabeled [3H]paclitaxel accumulation assay; clinical pharmacokinetic study with SNP genotyping","journal":"Clinical pharmacology and therapeutics","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — oocyte transport assay with panel of transporters identifies OATP1B3 as selective paclitaxel transporter, single lab, replicated panel approach","pmids":["17186002"],"is_preprint":false},{"year":2007,"finding":"Microcystin-LR is actively transported into cells via OATP1B3 (Km ~1.2 µM); OATP1B3-mediated uptake results in PP2A inhibition and apoptosis through activation of multiple MAPK pathways (ERK1/2, JNK, p38); cytotoxicity is blocked by MAPK inhibitors (U0126, SP600125, SB203580) and by OATP1B3 substrates/inhibitors.","method":"HEK293 cells stably expressing OATP1B3; radiolabeled microcystin-LR uptake assay; FACS apoptosis analysis; phosphatase activity assay; MAPK inhibitor studies","journal":"Toxicological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — uptake kinetics, pathway inhibitor studies, and mechanistic downstream signaling analysis, single lab, multiple methods","pmids":["17369605"],"is_preprint":false},{"year":2008,"finding":"OATP1B3 transports testosterone in a saturable, active manner; cells transfected with SLCO1B3 wild-type (334T/699G) transport testosterone, whereas the double-variant haplotype (334G/699A) impairs testosterone uptake, establishing a substrate-specific effect of this common haplotype.","method":"Cos-7 cell transfection with wild-type and variant SLCO1B3 constructs; testosterone transport assay; fluorescence microscopy for tissue expression","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional transport assay with defined variant constructs, single lab, direct mechanistic comparison of WT vs. variant","pmids":["18519758"],"is_preprint":false},{"year":2008,"finding":"OATP1B3 overexpression in colorectal cancer cells with wild-type p53 confers resistance to camptothecin- and oxaliplatin-induced apoptosis; this effect is dependent on transport activity (transport-dead G583E mutant lacks the antiapoptotic effect); OATP1B3 reduces p53 transcriptional activity and downstream targets p21WAF1 and PUMA.","method":"Stable overexpression in colorectal cancer cell lines (RKO, HCT-8, HCT116 p53+/+, p53-/-); cytotoxicity assay; TUNEL assay; p53 transcriptional activity reporter; RT-PCR and immunoblot for p53 targets; transport-dead G583E mutant control","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cell lines, transport-dead mutant control establishes transport-dependency, multiple readouts, single lab","pmids":["19074900"],"is_preprint":false},{"year":2012,"finding":"Complete simultaneous deficiency of OATP1B1 and OATP1B3 causes Rotor syndrome; OATP1B3 mediates hepatic reuptake of bilirubin conjugates secreted into blood by MRP3/ABCC3; transgenic expression of human OATP1B3 alone in Oatp1a/1b-deficient mice restores bilirubin conjugate clearance, confirming its independent sufficiency as a hepatic reuptake transporter.","method":"Genetic analysis of Rotor syndrome families (mutation identification); Oatp1a/1b knockout mice; Abcc3-knockout mice; OATP1B3-transgenic rescue experiments; plasma bilirubin measurement","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic disease mechanism confirmed by transgenic mouse rescue with individual human transporters, multiple genetic models, replicated across families and mouse experiments","pmids":["22232210"],"is_preprint":false},{"year":2012,"finding":"Three discrete structural regions of OATP1B3—transmembrane helices 1 and 10, and extracellular loop 6—determine substrate specificity for CCK-8; point mutations at three key residues in the corresponding positions of OATP1B1 confer gain-of-function CCK-8 transport without affecting atorvastatin or estrone sulfate transport.","method":"Homologous recombination-based chimeric transporter library in E. coli; site-directed mutagenesis; functional transport assays in transfected cells","journal":"Molecular pharmaceutics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structure-function mapping by systematic mutagenesis with gain-of-function demonstration, substrate specificity controls, single lab","pmids":["22352740"],"is_preprint":false},{"year":2012,"finding":"The cancer-specific OATP1B3 variant (V1/Ct-OATP1B3), which lacks the first 28 N-terminal amino acids compared to liver-type OATP1B3, localizes predominantly to the cytoplasm rather than the plasma membrane and shows only modest CCK-8 transport activity compared to wild-type OATP1B3; the variant undergoes different post-translational modifications and increased proteasomal degradation.","method":"RT-PCR identification of variant; exogenous expression in HEK293T cells; subcellular fractionation and immunoblotting; transport assay for CCK-8; proteasome inhibitor treatment","journal":"Molecular pharmaceutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by fractionation, functional transport assay, and post-translational analysis, single lab, multiple methods","pmids":["23215050"],"is_preprint":false},{"year":2013,"finding":"Wnt/β-catenin signalling activates OATP1B3 expression in HCC; LiCl treatment (Wnt activator) induced OATP1B3 mRNA in KYN-2 HCC cells; OATP1B3 expression correlates significantly with Wnt/β-catenin target gene expression in HCC clinical samples; OATP1B3 is the primary transporter mediating gadoxetic acid (Gd-EOB-DTPA) uptake in HCC.","method":"LiCl Wnt-pathway activation in KYN-2 cells; qRT-PCR and immunohistochemistry of clinical HCC samples; comprehensive transporter mRNA profiling; correlation analysis with Wnt target genes and EOB-MRI enhancement","journal":"Journal of hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro Wnt activation experiment plus clinical correlation, single lab, two orthogonal approaches","pmids":["24946283"],"is_preprint":false},{"year":2013,"finding":"Sorafenib-glucuronide is a substrate of OATP1B3 (6.4-fold uptake vs. control) and OATP1B1; plasma levels of sorafenib-glucuronide were increased >8-fold in Oatp1b2-knockout mice; expression of human OATP1B3 in knockout mice partially restored normal sorafenib-glucuronide pharmacokinetics.","method":"HEK293 cells stably expressing OATP1B3 or OATP1B1; Oatp1b2-knockout mice; OATP1B3-transgenic rescue mice; pharmacokinetic analysis; hepatic/intestinal microsome metabolism assay","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro transport assay confirmed by in vivo knockout/transgenic rescue, single lab","pmids":["23340295"],"is_preprint":false},{"year":2013,"finding":"Hypoxia inducible factor-1α (HIF-1α) drives transcription of cancer-specific OATP1B3 (csOATP1B3) via two functional hypoxia response elements (HREs) identified by reporter assays and EMSA; siRNA knockdown of HIF-1α substantially decreases csOATP1B3 expression; wild-type liver OATP1B3 is not induced by hypoxia.","method":"Luciferase reporter assays with deletion/mutated csOATP1B3 promoter constructs; EMSA with biotin-labeled HRE probe; siRNA knockdown; RT-PCR and immunoblotting; chromatin immunoprecipitation (CIP assay referenced in related study)","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — reporter assay, EMSA binding, and siRNA knockdown in combination, single lab, multiple orthogonal methods","pmids":["23924606"],"is_preprint":false},{"year":2014,"finding":"PKC activation (via PMA) rapidly decreases OATP1B3 transport activity without affecting total protein or mRNA levels or surface expression; the mechanism involves increased phosphorylation of OATP1B3 at Ser/Thr/Tyr residues; PKC inhibitor BIM I blocks PMA-induced inhibition, confirming PKC mediates the post-translational regulation.","method":"Human sandwich-cultured hepatocytes; adenoviral FLAG-Myc-tagged OATP1B3 transduction; surface biotinylation; anti-phospho-Ser/Thr/Tyr immunoprecipitation; radiolabeled CCK-8 accumulation assay; PKC inhibitor pretreatment","journal":"Drug metabolism and disposition","confidence":"High","confidence_rationale":"Tier 1 / Moderate — primary human hepatocytes, surface biotinylation, phosphorylation detection, and functional assay with specific inhibitor controls, single lab, multiple orthogonal methods","pmids":["25200870"],"is_preprint":false},{"year":2014,"finding":"OATP1B3 is expressed in pancreatic β-islet cells; glibenclamide is a substrate of OATP1B3; OATP1B3 overexpression in MIN6 murine β-cells enhances the insulinotropic effect of glibenclamide without affecting glucose-stimulated insulin secretion, establishing OATP1B3 as a determinant of glibenclamide efficacy at the tissue level.","method":"MDCKII cell transport assay; CCK-8 uptake inhibition assay; transient OATP1B3 overexpression in MIN6 cells; glucose-stimulated and glibenclamide-stimulated insulin secretion assay","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — substrate identification by uptake inhibition plus functional insulin secretion rescue assay, single lab, two orthogonal methods","pmids":["24150606"],"is_preprint":false},{"year":2016,"finding":"Loss of SLCO1B3 expression in prostate cancer drives taxane resistance; silencing SLCO1B3 in chemo-naive PC346C cells decreased intracellular docetaxel and cabazitaxel concentrations ~2-fold; SLCO1B3 overexpression increased sensitivity to both taxanes; SLCO1B3 was significantly downregulated in docetaxel-resistant patient-derived xenografts with decreased intratumoural drug concentrations.","method":"Patient-derived xenograft models; next-generation sequencing; siRNA knockdown; SLCO1B3 overexpression; [14C]-docetaxel and [14C]-cabazitaxel uptake assays; cytotoxicity assays","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional manipulation (knockdown and overexpression) with direct drug uptake measurement in PDX and cell models, single lab","pmids":["27537383"],"is_preprint":false},{"year":2017,"finding":"The N-terminal region of OATP1B3 (amino acids 12–28) is essential for plasma membrane trafficking; the first 50 N-terminal amino acids are sufficient to drive membrane localization; cancer-type OATP1B3 variant lacking the first 28 amino acids is cytoplasmic, consistent with the N-terminal requirement; this property is shared with OATP1B1 and rat Oatp1b2.","method":"N-terminal truncation and point mutants expressed in HEK293T, HCT-8, and MDCK II cells; subcellular fractionation and immunoblotting; N-terminal fusion constructs","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic truncation mutagenesis in three cell lines, single lab, direct fractionation assay","pmids":["28216016"],"is_preprint":false},{"year":2017,"finding":"OATP1B3 mediates testosterone influx with Km = 23.2 µmol/L and Vmax = 321.6 pmol/mg/min; in vivo, Slco1b2-/-/hSLCO1B3 knock-in mice have greater hepatic testosterone uptake and lower plasma testosterone exposure than Slco1b2-/- mice; SLCO1B3 is the second-most differentially expressed transporter in CRPC vs. androgen-sensitive cells (116-fold).","method":"Doxycycline-inducible SLCO1B3 cell system; [3H]-testosterone uptake with kinetic analysis; Slco1b2-/- and hSLCO1B3 knock-in mouse pharmacokinetic studies; siRNA knockdown in CRPC cells","journal":"Molecular cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — kinetic parameters in inducible cell system confirmed by in vivo transgenic knock-in pharmacokinetics, multiple methods, single lab","pmids":["28389619"],"is_preprint":false},{"year":2020,"finding":"OATP1B3 forms hetero-oligomers with OCT1, OATP1B1, and NTCP; co-expression with OCT1 decreases OATP1B3 plasma membrane expression but increases apparent CCK-8 turnover rate; co-expression with OATP1B1 or NTCP increases membrane expression but decreases turnover rate; OCT1 knockdown in human hepatocytes increases OATP1B3 function.","method":"Co-immunoprecipitation from human hepatocytes; proximity ligation assay in HEK293 cells and human liver sections; surface biotinylation; CCK-8 transport assay; siRNA OCT1 knockdown in human hepatocytes","journal":"Drug metabolism and disposition","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction demonstrated by co-IP and PLA in native liver tissue plus functional consequences in knockdown/co-expression, single lab, multiple orthogonal methods","pmids":["32482756"],"is_preprint":false},{"year":2021,"finding":"abiraterone treatment induces SLCO1B3 expression in prostate cancer cells (22Rv1) in vitro and in xenografts in vivo; the mechanism involves abiraterone-mediated downregulation of hsa-miR-579-3p, which normally suppresses SLCO1B3; hsa-miR-579-3p was confirmed to bind the SLCO1B3 3'UTR and inhibit its expression by dual luciferase reporter assay.","method":"qPCR in prostate cancer cell lines; NanoString miRNA profiling; TargetScan/miRanda prediction; dual luciferase reporter assay with SLCO1B3 3'UTR; 22Rv1 xenograft model in vivo","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter confirms miRNA binding to 3'UTR, in vitro and in vivo abiraterone induction, single lab, multiple methods","pmids":["34031488"],"is_preprint":false},{"year":2022,"finding":"Cancer-type OATP1B3 (Ct-OATP1B3) directly interacts with IGF2BP2 (an RNA-binding protein); this interaction stabilizes CPT1A and NDUFA2 mRNAs, increasing their expression and thereby elevating mitochondrial fatty acid β-oxidation and oxidative phosphorylation, which promotes ATP production and lamellipodia formation to drive ovarian cancer cell migration and invasion.","method":"Co-immunoprecipitation of Ct-OATP1B3 with IGF2BP2; RNA-binding protein pulldown; mRNA stability assay; seahorse metabolic assay; lamellipodia imaging; in vivo xenograft metastasis model; siRNA knockdown","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP interaction, mRNA stability, metabolic assay, and in vivo functional validation, single lab, multiple orthogonal methods","pmids":["35717493"],"is_preprint":false}],"current_model":"OATP1B3 (SLCO1B3) is a multispecific, Na+-independent organic anion uptake transporter expressed at the basolateral (sinusoidal) membrane of hepatocytes, where its membrane localization depends on its N-terminal 12–28 amino acid region; it transports a broad range of substrates (bile acids, bilirubin, bilirubin conjugates, steroid hormones including testosterone, CCK-8, statins, telmisartan, paclitaxel, docetaxel, and numerous drugs) in concert with apical export pumps MRP2/ABCC2 to achieve vectorial hepatobiliary elimination; in the liver-blood shuttle, OATP1B3 (together with OATP1B1) mediates reuptake of MRP3-secreted bilirubin conjugates, and its complete dual deficiency causes Rotor syndrome; its transport activity is post-translationally regulated by PKC-mediated phosphorylation and by hetero-oligomerization with OATP1B1, NTCP, and OCT1; substrate specificity for CCK-8 (vs. OATP1B1) is governed by three discrete regions involving TM helices 1 and 10 and extracellular loop 6; a cancer-specific splice variant (Ct-OATP1B3) lacking the first 28 N-terminal amino acids is cytoplasmic and has reduced transport activity but gains a non-transport function through interaction with IGF2BP2 to promote metabolic reprogramming; OATP1B3 transcription is repressed by HNF3β/FOXA2, induced by Wnt/β-catenin signalling and HIF-1α (in cancer), and post-transcriptionally regulated by miR-579-3p."},"narrative":{"mechanistic_narrative":"OATP1B3 (SLCO1B3) is a multispecific, Na+-independent organic anion uptake transporter of the hepatocyte basolateral (sinusoidal) membrane that, together with the apical export pump MRP2/ABCC2, drives vectorial hepatobiliary elimination of its substrates [PMID:11641421, PMID:12695556]. Its substrate range is broad and includes bilirubin and bile acid conjugates, steroid hormones such as testosterone, the peptide CCK-8, and numerous drugs including statins, telmisartan, paclitaxel, taxanes, and microcystin-LR [PMID:12568656, PMID:15665139, PMID:16611857, PMID:17186002, PMID:18519758]. Substrate selectivity is encoded in discrete structural elements—transmembrane helices 1 and 10 and extracellular loop 6 govern CCK-8 recognition, and individual residue substitutions abolish bile acid transport while sparing other substrates [PMID:15226676, PMID:22352740]. In the liver-blood shuttle, OATP1B3 mediates hepatic reuptake of bilirubin conjugates secreted into blood by MRP3/ABCC3; transgenic human OATP1B3 alone rescues bilirubin conjugate clearance in Oatp-deficient mice, and complete combined OATP1B1/OATP1B3 deficiency causes Rotor syndrome [PMID:22232210]. Plasma membrane targeting requires the N-terminal 12–28 amino acid region [PMID:28216016]. Transport activity is regulated post-translationally by PKC-mediated phosphorylation, which suppresses function without changing surface expression, and by hetero-oligomerization with OCT1, OATP1B1, and NTCP that reciprocally tune membrane abundance and turnover [PMID:25200870, PMID:32482756]. SLCO1B3 transcription is repressed by HNF3β/FOXA2 and, in cancer, induced by Wnt/β-catenin and HIF-1α signalling, with additional post-transcriptional control by miR-579-3p [PMID:14739090, PMID:24946283, PMID:23924606, PMID:34031488]. A cancer-specific N-terminally truncated variant (Ct-OATP1B3) is cytoplasmic with reduced transport activity but acquires a non-transport function by binding IGF2BP2 to stabilize CPT1A/NDUFA2 mRNAs and reprogram metabolism, promoting cancer cell migration [PMID:23215050, PMID:35717493].","teleology":[{"year":2001,"claim":"Establishing that OATP1B3 is a basolateral hepatocyte uptake transporter cooperating with an apical export pump defined its core role in vectorial hepatobiliary elimination.","evidence":"Double-transfected MDCK Transwell transport with OATP1B3 + MRP2, immunofluorescence localization, multiple substrate uptake","pmids":["11641421"],"confidence":"High","gaps":["Did not resolve transport stoichiometry or driving ion","Substrate spectrum at this point partial"]},{"year":2003,"claim":"Localization to the sinusoidal hepatocyte membrane and demonstration of bilirubin/estradiol transport tied OATP1B3 to physiological organic anion and bilirubin handling.","evidence":"Immunofluorescence/IHC on human liver and tumors; Xenopus oocyte kinetic uptake of unconjugated bilirubin","pmids":["12695556","12568656"],"confidence":"Medium","gaps":["Tumor expression pattern not mechanistically explained","Placental role inferred from mRNA only"]},{"year":2004,"claim":"Mutagenesis distinguished trafficking-defective from substrate-selective effects, showing OATP1B3 residues differentially control localization versus transport of specific substrates.","evidence":"Site-directed mutagenesis (G522C, G583E, S112A, M233I) with localization and radiolabeled transport assays in MDCKII/HEK293","pmids":["15226676"],"confidence":"High","gaps":["Structural basis of substrate-selective loss not defined","G522C/G583E are rare/artificial mutations"]},{"year":2004,"claim":"Identification of HNF3β/FOXA2 as a promoter-binding repressor provided the first transcriptional control mechanism and a link to its loss in HCC.","evidence":"Luciferase reporter, EMSA mapping to -39/-23, clinical HCC correlation","pmids":["14739090"],"confidence":"High","gaps":["Upstream signals controlling HNF3β not addressed","Causality in HCC not tested functionally"]},{"year":2005,"claim":"Reconstitution of CCK-8 vectorial transport defined a high-affinity peptide substrate and provided the canonical functional reporter used in later mechanistic studies.","evidence":"Double-transfected MDCKII Transwell assay, MRP2 vesicle ATP-dependent transport, cyclosporin A inhibition","pmids":["15665139"],"confidence":"High","gaps":["Physiological significance of hepatic CCK-8 clearance unclear"]},{"year":2006,"claim":"Expanding the substrate set to multiple drugs and bile acid conjugates and demonstrating GSH-coupled cotransport established OATP1B3 as a broad, possibly bidirectional, anion carrier.","evidence":"HEK293/oocyte/CHO uptake kinetics, human hepatocyte validation, GSH cotransport stoichiometry analysis, EHBR rat in vivo","pmids":["16611857","16501004","16686371","16877380","17496208"],"confidence":"Medium","gaps":["Bidirectional/export function shown only in oocytes","GSH cotransport not validated in native membrane"]},{"year":2007,"claim":"Demonstrating selective transport of paclitaxel and active uptake of the toxin microcystin-LR linked OATP1B3 both to chemotherapeutic disposition and to toxin-mediated cell death signalling.","evidence":"Oocyte transporter panel for paclitaxel; HEK293 microcystin-LR uptake with PP2A/MAPK pathway and apoptosis readouts","pmids":["17186002","17369605"],"confidence":"Medium","gaps":["Paclitaxel SNP associations negative in patients","Microcystin downstream signalling specific to overexpression model"]},{"year":2008,"claim":"Testosterone transport and its impairment by a common haplotype, plus a transport-dependent antiapoptotic effect in p53-wildtype cancer cells, connected OATP1B3 to hormone handling and chemoresistance.","evidence":"Cos-7 WT vs variant testosterone transport; colorectal cancer overexpression with transport-dead G583E control and p53 reporter/target analysis","pmids":["18519758","19074900"],"confidence":"Medium","gaps":["Mechanism linking transport to p53 suppression not defined","Haplotype effect not confirmed in vivo here"]},{"year":2012,"claim":"Mapping substrate specificity to TM1/TM10/ECL6 and confirming Rotor syndrome via transgenic mouse rescue established both the structural logic of recognition and the in vivo physiological role in bilirubin reuptake.","evidence":"Chimeric/mutant transporter library with gain-of-function CCK-8 transport; Rotor family genetics with Oatp1a/1b-null and OATP1B3-transgenic rescue mice","pmids":["22352740","22232210"],"confidence":"High","gaps":["No high-resolution structure of the transporter","Substrate determinants mapped only for CCK-8"]},{"year":2012,"claim":"Characterizing the cancer-type variant lacking the first 28 N-terminal residues as cytoplasmic and transport-impaired set up a distinct, non-canonical role for OATP1B3 in tumors.","evidence":"RT-PCR variant identification, subcellular fractionation, CCK-8 transport, proteasome inhibitor treatment in HEK293T","pmids":["23215050"],"confidence":"Medium","gaps":["Function of cytoplasmic variant not yet defined at this stage","Truncation origin (splicing) mechanism not detailed here"]},{"year":2013,"claim":"Identifying Wnt/β-catenin and HIF-1α as cancer-context inducers and a sorafenib-glucuronide substrate role expanded the regulatory and pharmacologic picture in tumors.","evidence":"LiCl Wnt activation + HCC correlation; HIF-1α HRE reporter/EMSA/siRNA on cancer-specific promoter; HEK293 transport + Oatp1b2-null/transgenic mouse PK for sorafenib-glucuronide","pmids":["24946283","23924606","23340295"],"confidence":"Medium","gaps":["Wnt-to-promoter signalling steps not fully traced","Cancer-specific vs liver-type promoter usage requires further dissection"]},{"year":2014,"claim":"Demonstrating PKC-mediated phosphorylation that suppresses activity without altering surface expression revealed acute post-translational control of transport function.","evidence":"Sandwich-cultured human hepatocytes, surface biotinylation, anti-phospho IP, CCK-8 assay, PKC inhibitor BIM I","pmids":["25200870"],"confidence":"High","gaps":["Specific phosphorylated residues not mapped","Physiological trigger of PKC regulation unknown"]},{"year":2014,"claim":"Showing β-islet expression and glibenclamide transport that enhances insulinotropic effect extended OATP1B3 function beyond liver to tissue-level drug action.","evidence":"MDCKII transport, CCK-8 inhibition, MIN6 overexpression with insulin secretion assay","pmids":["24150606"],"confidence":"Medium","gaps":["Endogenous β-cell expression level/relevance not quantified","Single rodent β-cell model"]},{"year":2016,"claim":"Bidirectional manipulation in prostate cancer models established that loss of SLCO1B3 reduces intratumoural taxane levels and drives resistance.","evidence":"PDX and PC346C models, siRNA knockdown and overexpression, [14C]-docetaxel/cabazitaxel uptake and cytotoxicity","pmids":["27537383"],"confidence":"Medium","gaps":["Regulatory cause of expression loss in resistant tumors not defined here"]},{"year":2017,"claim":"Defining the N-terminal 12-28 region as required for membrane trafficking and quantifying testosterone uptake in vivo linked transporter localization, androgen disposition, and prostate cancer biology.","evidence":"N-terminal truncation/fusion mutants with fractionation in three cell lines; inducible cell kinetics and Slco1b2-/-/hSLCO1B3 knock-in mouse testosterone PK; CRPC siRNA","pmids":["28216016","28389619"],"confidence":"High","gaps":["Trafficking machinery recognizing the N-terminus not identified","Mechanism of CRPC upregulation not resolved here"]},{"year":2020,"claim":"Demonstrating hetero-oligomerization with OCT1, OATP1B1, and NTCP that reciprocally alters membrane expression and turnover revealed transporter-transporter interplay as a functional regulator.","evidence":"Co-IP from human hepatocytes, proximity ligation in liver sections, surface biotinylation, CCK-8 transport, OCT1 knockdown","pmids":["32482756"],"confidence":"Medium","gaps":["Oligomer interface/stoichiometry not structurally defined","Physiological extent of regulation in vivo unclear"]},{"year":2021,"claim":"Identifying miR-579-3p as a 3'UTR-binding repressor whose abiraterone-induced downregulation upregulates SLCO1B3 added a post-transcriptional layer relevant to prostate cancer therapy.","evidence":"qPCR, NanoString miRNA profiling, dual luciferase 3'UTR reporter, 22Rv1 xenograft","pmids":["34031488"],"confidence":"Medium","gaps":["Upstream control of miR-579-3p by abiraterone not fully mechanistic","Clinical relevance to drug exposure untested"]},{"year":2022,"claim":"Establishing that the cytoplasmic cancer variant binds IGF2BP2 to stabilize metabolic mRNAs assigned Ct-OATP1B3 a transport-independent moonlighting function driving cancer metabolic reprogramming and invasion.","evidence":"Co-IP, RNA-binding pulldown, mRNA stability and Seahorse metabolic assays, lamellipodia imaging, in vivo metastasis xenograft, siRNA","pmids":["35717493"],"confidence":"Medium","gaps":["Direct vs indirect binding to CPT1A/NDUFA2 transcripts not resolved","Generality beyond ovarian cancer unknown"]},{"year":null,"claim":"A high-resolution structure defining the transport mechanism, ion coupling, and the molecular basis of multispecific substrate recognition across the full substrate range remains unestablished.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No experimental atomic structure in the corpus","Specificity determinants mapped only for CCK-8","Coupling ions/driving force not fully defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,2,6,7,9,10,12,14,26]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0,2,16]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[29]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,25]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[18,25,29]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,6,16]},{"term_id":"R-HSA-9748784","term_label":"Drug ADME","supporting_discovery_ids":[3,7,11,12,20,24]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,16,29]}],"complexes":[],"partners":["SLCO1B1","SLC22A1","SLC10A1","ABCC2","IGF2BP2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NPD5","full_name":"Solute carrier organic anion transporter family member 1B3","aliases":["Liver-specific organic anion transporter 2","LST-2","OATP1B3","Organic anion transporter 8","Organic anion-transporting polypeptide 8","OATP-8","Solute carrier family 21 member 8"],"length_aa":702,"mass_kda":77.4,"function":"Mediates the Na(+)-independent uptake of organic anions (PubMed:10779507, PubMed:15159445, PubMed:17412826). Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (17-beta-glucuronosyl estradiol, dehydroepiandrosterone sulfate (DHEAS), and estrone 3-sulfate), as well as eicosanoid leukotriene C4, prostaglandin E2 and L-thyroxine (T4) (PubMed:10779507, PubMed:11159893, PubMed:12568656, PubMed:15159445, PubMed:17412826, PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463). Shows a pH-sensitive substrate specificity towards sulfated steroids, taurocholate and T4 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). Involved in the clearance of bile acids and organic anions from the liver (PubMed:22232210). Can take up bilirubin glucuronides from plasma into the liver, contributing to the detoxification-enhancing liver-blood shuttling loop (PubMed:22232210). Transports coproporphyrin I and III, by-products of heme synthesis, and may be involved in their hepatic disposition (PubMed:26383540). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can transport HMG-CoA reductase inhibitors (also known as statins) such as pitavastatin, a clinically important class of hypolipidemic drugs (PubMed:15159445). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drugs methotrexate and paclitaxel (PubMed:23243220). May also transport antihypertension agents, such as the angiotensin-converting enzyme (ACE) inhibitor prodrug enalapril, and the highly selective angiotensin II AT1-receptor antagonist valsartan, in the liver (PubMed:16624871, PubMed:16627748)","subcellular_location":"Basolateral cell membrane; Basal cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9NPD5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLCO1B3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SLCO1B3","total_profiled":1310},"omim":[{"mim_id":"619875","title":"SOLUTE CARRIER ORGANIC ANION TRANSPORTER FAMILY, MEMBER 1B7; SLCO1B7","url":"https://www.omim.org/entry/619875"},{"mim_id":"613389","title":"SOLUTE CARRIER ORGANIC ANION TRANSPORTER FAMILY, MEMBER 1C1; SLCO1C1","url":"https://www.omim.org/entry/613389"},{"mim_id":"605495","title":"SOLUTE CARRIER ORGANIC ANION TRANSPORTER FAMILY, MEMBER 1B3; SLCO1B3","url":"https://www.omim.org/entry/605495"},{"mim_id":"604843","title":"SOLUTE CARRIER ORGANIC ANION TRANSPORTER FAMILY, MEMBER 1B1; SLCO1B1","url":"https://www.omim.org/entry/604843"},{"mim_id":"601816","title":"BILIRUBIN, SERUM LEVEL OF, QUANTITATIVE TRAIT LOCUS 1; BILIQTL1","url":"https://www.omim.org/entry/601816"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"liver","ntpm":247.7}],"url":"https://www.proteinatlas.org/search/SLCO1B3"},"hgnc":{"alias_symbol":["OATP8","OATP1B3"],"prev_symbol":["SLC21A8"]},"alphafold":{"accession":"Q9NPD5","domains":[{"cath_id":"1.20.1250.20","chopping":"25-124_168-288","consensus_level":"medium","plddt":89.7534,"start":25,"end":288},{"cath_id":"1.20.1250.20","chopping":"331-431_528-673","consensus_level":"medium","plddt":88.7535,"start":331,"end":673},{"cath_id":"-","chopping":"435-526","consensus_level":"medium","plddt":84.1801,"start":435,"end":526}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NPD5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NPD5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NPD5-F1-predicted_aligned_error_v6.png","plddt_mean":79.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLCO1B3","jax_strain_url":"https://www.jax.org/strain/search?query=SLCO1B3"},"sequence":{"accession":"Q9NPD5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NPD5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NPD5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NPD5"}},"corpus_meta":[{"pmid":"15159445","id":"PMC_15159445","title":"Contribution 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basolateral uptake of organic anions (BSP, leukotriene C4, 17β-glucuronosyl estradiol, DHEA-S, fluo-3, rifampicin) in hepatocytes; vectorial transcellular transport from basolateral to apical compartment was reconstituted in double-transfected MDCK cells co-expressing OATP1B3 at the basolateral membrane and ABCC2/MRP2 at the apical membrane, demonstrating cooperative hepatobiliary elimination.\",\n      \"method\": \"Double-transfected MDCK cell Transwell transport assay; immunoblotting; confocal laser scanning microscopy for protein localization\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted vectorial transport in a defined double-transfected cell system with multiple substrates, immunofluorescence localization, and direct transport measurement\",\n      \"pmids\": [\"11641421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"OATP1B3 (SLC21A8/OATP8) is localized to the basolateral (sinusoidal) membrane of human hepatocytes; both OATP1B3 and OATP1B1 were detected in hepatocellular carcinoma with irregular staining pattern but absent in HepG2 cells and absent in cholangiocarcinoma/colorectal/pancreatic liver metastases.\",\n      \"method\": \"Immunoblot, immunoprecipitation, immunofluorescence microscopy with monoclonal antibodies; immunohistochemistry on paraffin sections of liver tumors\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by immunofluorescence and IHC with characterized antibodies, single lab, multiple methods\",\n      \"pmids\": [\"12695556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"OATP1B3 (OATP-8) transports unconjugated bilirubin (UCB) and 17β-glucuronosyl estradiol in a carrier-mediated, saturable manner when expressed in Xenopus laevis oocytes; OATP1B3 mRNA is expressed in human placental trophoblasts suggesting a role in fetal UCB clearance via the placenta-maternal liver tandem.\",\n      \"method\": \"Xenopus oocyte expression system; radiolabeled substrate uptake assay; RT-PCR and real-time quantitative RT-PCR; kinetic analysis\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro transport reconstitution in oocytes with kinetics, single lab\",\n      \"pmids\": [\"12568656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"OATP1B3 mediates Na+-independent, saturable uptake of pitavastatin (Km ~3.3 µM) in HEK293 cells; OATP1B1 accounts for ~90% of total hepatic uptake of pitavastatin in humans based on relative activity factor methodology.\",\n      \"method\": \"Transporter-expressing HEK293 cells; radiolabeled uptake assay; Western blot for relative expression; cryopreserved human hepatocyte uptake assay\",\n      \"journal\": \"The Journal of pharmacology and experimental therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — uptake kinetics in transfected cells plus human hepatocyte validation, single lab, two orthogonal methods\",\n      \"pmids\": [\"15159445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Mutations in SLCO1B3 have substrate-specific functional consequences: OATP1B3-G522C and OATP1B3-G583E (rare/artificial mutations) are retained intracellularly and abolish bile acid transport but retain transport of BSP; common polymorphisms S112A and M233I show normal lateral membrane localization and comparable transport activity.\",\n      \"method\": \"Site-directed mutagenesis; stable transfection in MDCKII and HEK293 cells; immunofluorescence for localization; radiolabeled substrate transport assays\",\n      \"journal\": \"Pharmacogenetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis combined with localization and functional transport assays in two cell systems, rigorous controls\",\n      \"pmids\": [\"15226676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"HNF3β (FOXA2) transcriptionally represses the SLCO1B3 (OATP8) gene promoter; an HNF3β binding site was mapped to nucleotides -39/-23 of the OATP8 promoter by EMSA; HNF3β cotransfection reduced OATP8 promoter activity by ~70% in Huh7 cells and inversely correlated with OATP8 mRNA/protein in HCC.\",\n      \"method\": \"Luciferase reporter assay; electrophoretic mobility shift assay (EMSA); real-time PCR; Western blot; correlation analysis in 13 paired HCC/non-tumor liver samples\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — EMSA binding site mapping plus functional reporter assay plus clinical correlation, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"14739090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"OATP1B3 mediates high-affinity, saturable uptake of the peptide CCK-8 (cholecystokinin-8) at the basolateral membrane; vectorial transport of CCK-8 across MDCK cells requires both OATP1B3 (uptake) and ABCC2/MRP2 (apical efflux); MRP2 transports CCK-8 with Km = 8.1 µM in an ATP-dependent manner; cyclosporin A inhibits OATP1B3 uptake (Ki = 1.2 µM).\",\n      \"method\": \"Double-transfected MDCKII Transwell vectorial transport assay; membrane vesicle ATP-dependent transport assay; immunofluorescence microscopy; radiolabeled substrate uptake\",\n      \"journal\": \"The Journal of pharmacology and experimental therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted vectorial transport in defined double-transfected system, ATP-dependent vesicle assay for MRP2, kinetic parameters determined, rigorous controls\",\n      \"pmids\": [\"15665139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"OATP1B3 is the predominant transporter for hepatic uptake of telmisartan (Km = 0.81 µM) in humans; OATP1B1-expressing cells showed no significant uptake; selective inhibition with estrone-3-sulfate in human hepatocytes confirmed OATP1B3 predominance.\",\n      \"method\": \"HEK293 cells stably expressing OATP1B1 or OATP1B3; cryopreserved human hepatocyte uptake assay; selective inhibition studies; kinetic analysis\",\n      \"journal\": \"Drug metabolism and disposition\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — uptake kinetics in transfected cells confirmed in human hepatocytes with selective inhibitor, multiple orthogonal methods, replicated across systems\",\n      \"pmids\": [\"16611857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"OATP1B3 mediates Na+-independent, saturable uptake of olmesartan (Km = 71.8 µM) in Xenopus oocytes; OATP1B1 also transports olmesartan (Km = 42.6 µM); biliary excretion is mediated by MRP2 as shown by drastically reduced cumulative biliary excretion in EHBR (mrp2-deficient) rats.\",\n      \"method\": \"Xenopus oocyte expression; radiolabeled transport assay; EHBR rat in vivo model; canalicular membrane vesicle ATP-dependent transport assay; MRP2-expressing vesicles\",\n      \"journal\": \"Drug metabolism and disposition\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — oocyte transport assay plus in vivo EHBR rat model plus vesicle assay, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"16501004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"OATP1B3 transports TUDC and GUDC (bile acid conjugates) but not unconjugated UDCA in HEK293 expression systems; NTCP also transports UDCA and its conjugates; differential Na+-dependent and -independent contributions to hepatic uptake of UDCA conjugates were established.\",\n      \"method\": \"Transporter-expressing HEK293 cells; radiolabeled substrate uptake assay; Na+ replacement experiments; cryopreserved human hepatocyte uptake assays\",\n      \"journal\": \"Molecular pharmaceutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — uptake assays in transfected cells validated in human hepatocytes, single lab, two orthogonal systems\",\n      \"pmids\": [\"16686371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"OATP1B3 (OATP8/1B3) can mediate bile acid efflux in a glutathione-dependent manner: GSH cis-stimulates OATP1B3-mediated bile acid transport and is itself co-transported with a stoichiometry of 2:1 (GSH:bile acid); this cotransport was not observed for OATP1B1, suggesting OATP1B3 may function as a bidirectional transporter acting as a basolateral organic anion export route.\",\n      \"method\": \"Xenopus oocyte expression system with cholic acid methyl ester loading; radiolabeled trans-activation/inhibition assays; kinetic analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution in oocytes with kinetic analysis of cotransport stoichiometry, single lab\",\n      \"pmids\": [\"16877380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Bosentan and its metabolite Ro 48-5033 are substrates of OATP1B3; cyclosporin A and rifampicin inhibit OATP1B3-mediated bosentan uptake with IC50 values below effective plasma concentrations; sildenafil also inhibits OATP1B3-mediated transport at supratherapeutic concentrations, establishing inhibition of hepatic uptake as the mechanism of drug-drug interactions.\",\n      \"method\": \"CHO cells stably expressing OATP1B1 and OATP1B3; radiolabeled uptake assay; IC50 determination; comparison with clinical plasma concentrations\",\n      \"journal\": \"Drug metabolism and disposition\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transport assays in transfected cells with IC50 determination, single lab, mechanistic DDI interpretation\",\n      \"pmids\": [\"17496208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"OATP1B3 is the only human OATP capable of transporting paclitaxel to a significant extent among OATP1A2, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, and NTCP tested; common SNPs 334T>G and 699G>A in SLCO1B3 were not associated with paclitaxel pharmacokinetics in European patients.\",\n      \"method\": \"Xenopus laevis oocyte cRNA injection; radiolabeled [3H]paclitaxel accumulation assay; clinical pharmacokinetic study with SNP genotyping\",\n      \"journal\": \"Clinical pharmacology and therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — oocyte transport assay with panel of transporters identifies OATP1B3 as selective paclitaxel transporter, single lab, replicated panel approach\",\n      \"pmids\": [\"17186002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Microcystin-LR is actively transported into cells via OATP1B3 (Km ~1.2 µM); OATP1B3-mediated uptake results in PP2A inhibition and apoptosis through activation of multiple MAPK pathways (ERK1/2, JNK, p38); cytotoxicity is blocked by MAPK inhibitors (U0126, SP600125, SB203580) and by OATP1B3 substrates/inhibitors.\",\n      \"method\": \"HEK293 cells stably expressing OATP1B3; radiolabeled microcystin-LR uptake assay; FACS apoptosis analysis; phosphatase activity assay; MAPK inhibitor studies\",\n      \"journal\": \"Toxicological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — uptake kinetics, pathway inhibitor studies, and mechanistic downstream signaling analysis, single lab, multiple methods\",\n      \"pmids\": [\"17369605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"OATP1B3 transports testosterone in a saturable, active manner; cells transfected with SLCO1B3 wild-type (334T/699G) transport testosterone, whereas the double-variant haplotype (334G/699A) impairs testosterone uptake, establishing a substrate-specific effect of this common haplotype.\",\n      \"method\": \"Cos-7 cell transfection with wild-type and variant SLCO1B3 constructs; testosterone transport assay; fluorescence microscopy for tissue expression\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional transport assay with defined variant constructs, single lab, direct mechanistic comparison of WT vs. variant\",\n      \"pmids\": [\"18519758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"OATP1B3 overexpression in colorectal cancer cells with wild-type p53 confers resistance to camptothecin- and oxaliplatin-induced apoptosis; this effect is dependent on transport activity (transport-dead G583E mutant lacks the antiapoptotic effect); OATP1B3 reduces p53 transcriptional activity and downstream targets p21WAF1 and PUMA.\",\n      \"method\": \"Stable overexpression in colorectal cancer cell lines (RKO, HCT-8, HCT116 p53+/+, p53-/-); cytotoxicity assay; TUNEL assay; p53 transcriptional activity reporter; RT-PCR and immunoblot for p53 targets; transport-dead G583E mutant control\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cell lines, transport-dead mutant control establishes transport-dependency, multiple readouts, single lab\",\n      \"pmids\": [\"19074900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Complete simultaneous deficiency of OATP1B1 and OATP1B3 causes Rotor syndrome; OATP1B3 mediates hepatic reuptake of bilirubin conjugates secreted into blood by MRP3/ABCC3; transgenic expression of human OATP1B3 alone in Oatp1a/1b-deficient mice restores bilirubin conjugate clearance, confirming its independent sufficiency as a hepatic reuptake transporter.\",\n      \"method\": \"Genetic analysis of Rotor syndrome families (mutation identification); Oatp1a/1b knockout mice; Abcc3-knockout mice; OATP1B3-transgenic rescue experiments; plasma bilirubin measurement\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic disease mechanism confirmed by transgenic mouse rescue with individual human transporters, multiple genetic models, replicated across families and mouse experiments\",\n      \"pmids\": [\"22232210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Three discrete structural regions of OATP1B3—transmembrane helices 1 and 10, and extracellular loop 6—determine substrate specificity for CCK-8; point mutations at three key residues in the corresponding positions of OATP1B1 confer gain-of-function CCK-8 transport without affecting atorvastatin or estrone sulfate transport.\",\n      \"method\": \"Homologous recombination-based chimeric transporter library in E. coli; site-directed mutagenesis; functional transport assays in transfected cells\",\n      \"journal\": \"Molecular pharmaceutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structure-function mapping by systematic mutagenesis with gain-of-function demonstration, substrate specificity controls, single lab\",\n      \"pmids\": [\"22352740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The cancer-specific OATP1B3 variant (V1/Ct-OATP1B3), which lacks the first 28 N-terminal amino acids compared to liver-type OATP1B3, localizes predominantly to the cytoplasm rather than the plasma membrane and shows only modest CCK-8 transport activity compared to wild-type OATP1B3; the variant undergoes different post-translational modifications and increased proteasomal degradation.\",\n      \"method\": \"RT-PCR identification of variant; exogenous expression in HEK293T cells; subcellular fractionation and immunoblotting; transport assay for CCK-8; proteasome inhibitor treatment\",\n      \"journal\": \"Molecular pharmaceutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by fractionation, functional transport assay, and post-translational analysis, single lab, multiple methods\",\n      \"pmids\": [\"23215050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Wnt/β-catenin signalling activates OATP1B3 expression in HCC; LiCl treatment (Wnt activator) induced OATP1B3 mRNA in KYN-2 HCC cells; OATP1B3 expression correlates significantly with Wnt/β-catenin target gene expression in HCC clinical samples; OATP1B3 is the primary transporter mediating gadoxetic acid (Gd-EOB-DTPA) uptake in HCC.\",\n      \"method\": \"LiCl Wnt-pathway activation in KYN-2 cells; qRT-PCR and immunohistochemistry of clinical HCC samples; comprehensive transporter mRNA profiling; correlation analysis with Wnt target genes and EOB-MRI enhancement\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro Wnt activation experiment plus clinical correlation, single lab, two orthogonal approaches\",\n      \"pmids\": [\"24946283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Sorafenib-glucuronide is a substrate of OATP1B3 (6.4-fold uptake vs. control) and OATP1B1; plasma levels of sorafenib-glucuronide were increased >8-fold in Oatp1b2-knockout mice; expression of human OATP1B3 in knockout mice partially restored normal sorafenib-glucuronide pharmacokinetics.\",\n      \"method\": \"HEK293 cells stably expressing OATP1B3 or OATP1B1; Oatp1b2-knockout mice; OATP1B3-transgenic rescue mice; pharmacokinetic analysis; hepatic/intestinal microsome metabolism assay\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro transport assay confirmed by in vivo knockout/transgenic rescue, single lab\",\n      \"pmids\": [\"23340295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Hypoxia inducible factor-1α (HIF-1α) drives transcription of cancer-specific OATP1B3 (csOATP1B3) via two functional hypoxia response elements (HREs) identified by reporter assays and EMSA; siRNA knockdown of HIF-1α substantially decreases csOATP1B3 expression; wild-type liver OATP1B3 is not induced by hypoxia.\",\n      \"method\": \"Luciferase reporter assays with deletion/mutated csOATP1B3 promoter constructs; EMSA with biotin-labeled HRE probe; siRNA knockdown; RT-PCR and immunoblotting; chromatin immunoprecipitation (CIP assay referenced in related study)\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reporter assay, EMSA binding, and siRNA knockdown in combination, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"23924606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PKC activation (via PMA) rapidly decreases OATP1B3 transport activity without affecting total protein or mRNA levels or surface expression; the mechanism involves increased phosphorylation of OATP1B3 at Ser/Thr/Tyr residues; PKC inhibitor BIM I blocks PMA-induced inhibition, confirming PKC mediates the post-translational regulation.\",\n      \"method\": \"Human sandwich-cultured hepatocytes; adenoviral FLAG-Myc-tagged OATP1B3 transduction; surface biotinylation; anti-phospho-Ser/Thr/Tyr immunoprecipitation; radiolabeled CCK-8 accumulation assay; PKC inhibitor pretreatment\",\n      \"journal\": \"Drug metabolism and disposition\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — primary human hepatocytes, surface biotinylation, phosphorylation detection, and functional assay with specific inhibitor controls, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"25200870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"OATP1B3 is expressed in pancreatic β-islet cells; glibenclamide is a substrate of OATP1B3; OATP1B3 overexpression in MIN6 murine β-cells enhances the insulinotropic effect of glibenclamide without affecting glucose-stimulated insulin secretion, establishing OATP1B3 as a determinant of glibenclamide efficacy at the tissue level.\",\n      \"method\": \"MDCKII cell transport assay; CCK-8 uptake inhibition assay; transient OATP1B3 overexpression in MIN6 cells; glucose-stimulated and glibenclamide-stimulated insulin secretion assay\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — substrate identification by uptake inhibition plus functional insulin secretion rescue assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"24150606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Loss of SLCO1B3 expression in prostate cancer drives taxane resistance; silencing SLCO1B3 in chemo-naive PC346C cells decreased intracellular docetaxel and cabazitaxel concentrations ~2-fold; SLCO1B3 overexpression increased sensitivity to both taxanes; SLCO1B3 was significantly downregulated in docetaxel-resistant patient-derived xenografts with decreased intratumoural drug concentrations.\",\n      \"method\": \"Patient-derived xenograft models; next-generation sequencing; siRNA knockdown; SLCO1B3 overexpression; [14C]-docetaxel and [14C]-cabazitaxel uptake assays; cytotoxicity assays\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional manipulation (knockdown and overexpression) with direct drug uptake measurement in PDX and cell models, single lab\",\n      \"pmids\": [\"27537383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The N-terminal region of OATP1B3 (amino acids 12–28) is essential for plasma membrane trafficking; the first 50 N-terminal amino acids are sufficient to drive membrane localization; cancer-type OATP1B3 variant lacking the first 28 amino acids is cytoplasmic, consistent with the N-terminal requirement; this property is shared with OATP1B1 and rat Oatp1b2.\",\n      \"method\": \"N-terminal truncation and point mutants expressed in HEK293T, HCT-8, and MDCK II cells; subcellular fractionation and immunoblotting; N-terminal fusion constructs\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic truncation mutagenesis in three cell lines, single lab, direct fractionation assay\",\n      \"pmids\": [\"28216016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"OATP1B3 mediates testosterone influx with Km = 23.2 µmol/L and Vmax = 321.6 pmol/mg/min; in vivo, Slco1b2-/-/hSLCO1B3 knock-in mice have greater hepatic testosterone uptake and lower plasma testosterone exposure than Slco1b2-/- mice; SLCO1B3 is the second-most differentially expressed transporter in CRPC vs. androgen-sensitive cells (116-fold).\",\n      \"method\": \"Doxycycline-inducible SLCO1B3 cell system; [3H]-testosterone uptake with kinetic analysis; Slco1b2-/- and hSLCO1B3 knock-in mouse pharmacokinetic studies; siRNA knockdown in CRPC cells\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — kinetic parameters in inducible cell system confirmed by in vivo transgenic knock-in pharmacokinetics, multiple methods, single lab\",\n      \"pmids\": [\"28389619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"OATP1B3 forms hetero-oligomers with OCT1, OATP1B1, and NTCP; co-expression with OCT1 decreases OATP1B3 plasma membrane expression but increases apparent CCK-8 turnover rate; co-expression with OATP1B1 or NTCP increases membrane expression but decreases turnover rate; OCT1 knockdown in human hepatocytes increases OATP1B3 function.\",\n      \"method\": \"Co-immunoprecipitation from human hepatocytes; proximity ligation assay in HEK293 cells and human liver sections; surface biotinylation; CCK-8 transport assay; siRNA OCT1 knockdown in human hepatocytes\",\n      \"journal\": \"Drug metabolism and disposition\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction demonstrated by co-IP and PLA in native liver tissue plus functional consequences in knockdown/co-expression, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"32482756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"abiraterone treatment induces SLCO1B3 expression in prostate cancer cells (22Rv1) in vitro and in xenografts in vivo; the mechanism involves abiraterone-mediated downregulation of hsa-miR-579-3p, which normally suppresses SLCO1B3; hsa-miR-579-3p was confirmed to bind the SLCO1B3 3'UTR and inhibit its expression by dual luciferase reporter assay.\",\n      \"method\": \"qPCR in prostate cancer cell lines; NanoString miRNA profiling; TargetScan/miRanda prediction; dual luciferase reporter assay with SLCO1B3 3'UTR; 22Rv1 xenograft model in vivo\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter confirms miRNA binding to 3'UTR, in vitro and in vivo abiraterone induction, single lab, multiple methods\",\n      \"pmids\": [\"34031488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cancer-type OATP1B3 (Ct-OATP1B3) directly interacts with IGF2BP2 (an RNA-binding protein); this interaction stabilizes CPT1A and NDUFA2 mRNAs, increasing their expression and thereby elevating mitochondrial fatty acid β-oxidation and oxidative phosphorylation, which promotes ATP production and lamellipodia formation to drive ovarian cancer cell migration and invasion.\",\n      \"method\": \"Co-immunoprecipitation of Ct-OATP1B3 with IGF2BP2; RNA-binding protein pulldown; mRNA stability assay; seahorse metabolic assay; lamellipodia imaging; in vivo xenograft metastasis model; siRNA knockdown\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP interaction, mRNA stability, metabolic assay, and in vivo functional validation, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"35717493\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"OATP1B3 (SLCO1B3) is a multispecific, Na+-independent organic anion uptake transporter expressed at the basolateral (sinusoidal) membrane of hepatocytes, where its membrane localization depends on its N-terminal 12–28 amino acid region; it transports a broad range of substrates (bile acids, bilirubin, bilirubin conjugates, steroid hormones including testosterone, CCK-8, statins, telmisartan, paclitaxel, docetaxel, and numerous drugs) in concert with apical export pumps MRP2/ABCC2 to achieve vectorial hepatobiliary elimination; in the liver-blood shuttle, OATP1B3 (together with OATP1B1) mediates reuptake of MRP3-secreted bilirubin conjugates, and its complete dual deficiency causes Rotor syndrome; its transport activity is post-translationally regulated by PKC-mediated phosphorylation and by hetero-oligomerization with OATP1B1, NTCP, and OCT1; substrate specificity for CCK-8 (vs. OATP1B1) is governed by three discrete regions involving TM helices 1 and 10 and extracellular loop 6; a cancer-specific splice variant (Ct-OATP1B3) lacking the first 28 N-terminal amino acids is cytoplasmic and has reduced transport activity but gains a non-transport function through interaction with IGF2BP2 to promote metabolic reprogramming; OATP1B3 transcription is repressed by HNF3β/FOXA2, induced by Wnt/β-catenin signalling and HIF-1α (in cancer), and post-transcriptionally regulated by miR-579-3p.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"OATP1B3 (SLCO1B3) is a multispecific, Na+-independent organic anion uptake transporter of the hepatocyte basolateral (sinusoidal) membrane that, together with the apical export pump MRP2/ABCC2, drives vectorial hepatobiliary elimination of its substrates [#0, #1]. Its substrate range is broad and includes bilirubin and bile acid conjugates, steroid hormones such as testosterone, the peptide CCK-8, and numerous drugs including statins, telmisartan, paclitaxel, taxanes, and microcystin-LR [#2, #6, #7, #12, #14]. Substrate selectivity is encoded in discrete structural elements—transmembrane helices 1 and 10 and extracellular loop 6 govern CCK-8 recognition, and individual residue substitutions abolish bile acid transport while sparing other substrates [#4, #17]. In the liver-blood shuttle, OATP1B3 mediates hepatic reuptake of bilirubin conjugates secreted into blood by MRP3/ABCC3; transgenic human OATP1B3 alone rescues bilirubin conjugate clearance in Oatp-deficient mice, and complete combined OATP1B1/OATP1B3 deficiency causes Rotor syndrome [#16]. Plasma membrane targeting requires the N-terminal 12–28 amino acid region [#25]. Transport activity is regulated post-translationally by PKC-mediated phosphorylation, which suppresses function without changing surface expression, and by hetero-oligomerization with OCT1, OATP1B1, and NTCP that reciprocally tune membrane abundance and turnover [#22, #27]. SLCO1B3 transcription is repressed by HNF3β/FOXA2 and, in cancer, induced by Wnt/β-catenin and HIF-1α signalling, with additional post-transcriptional control by miR-579-3p [#5, #19, #21, #28]. A cancer-specific N-terminally truncated variant (Ct-OATP1B3) is cytoplasmic with reduced transport activity but acquires a non-transport function by binding IGF2BP2 to stabilize CPT1A/NDUFA2 mRNAs and reprogram metabolism, promoting cancer cell migration [#18, #29].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing that OATP1B3 is a basolateral hepatocyte uptake transporter cooperating with an apical export pump defined its core role in vectorial hepatobiliary elimination.\",\n      \"evidence\": \"Double-transfected MDCK Transwell transport with OATP1B3 + MRP2, immunofluorescence localization, multiple substrate uptake\",\n      \"pmids\": [\"11641421\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve transport stoichiometry or driving ion\", \"Substrate spectrum at this point partial\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Localization to the sinusoidal hepatocyte membrane and demonstration of bilirubin/estradiol transport tied OATP1B3 to physiological organic anion and bilirubin handling.\",\n      \"evidence\": \"Immunofluorescence/IHC on human liver and tumors; Xenopus oocyte kinetic uptake of unconjugated bilirubin\",\n      \"pmids\": [\"12695556\", \"12568656\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tumor expression pattern not mechanistically explained\", \"Placental role inferred from mRNA only\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Mutagenesis distinguished trafficking-defective from substrate-selective effects, showing OATP1B3 residues differentially control localization versus transport of specific substrates.\",\n      \"evidence\": \"Site-directed mutagenesis (G522C, G583E, S112A, M233I) with localization and radiolabeled transport assays in MDCKII/HEK293\",\n      \"pmids\": [\"15226676\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of substrate-selective loss not defined\", \"G522C/G583E are rare/artificial mutations\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identification of HNF3β/FOXA2 as a promoter-binding repressor provided the first transcriptional control mechanism and a link to its loss in HCC.\",\n      \"evidence\": \"Luciferase reporter, EMSA mapping to -39/-23, clinical HCC correlation\",\n      \"pmids\": [\"14739090\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals controlling HNF3β not addressed\", \"Causality in HCC not tested functionally\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Reconstitution of CCK-8 vectorial transport defined a high-affinity peptide substrate and provided the canonical functional reporter used in later mechanistic studies.\",\n      \"evidence\": \"Double-transfected MDCKII Transwell assay, MRP2 vesicle ATP-dependent transport, cyclosporin A inhibition\",\n      \"pmids\": [\"15665139\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological significance of hepatic CCK-8 clearance unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Expanding the substrate set to multiple drugs and bile acid conjugates and demonstrating GSH-coupled cotransport established OATP1B3 as a broad, possibly bidirectional, anion carrier.\",\n      \"evidence\": \"HEK293/oocyte/CHO uptake kinetics, human hepatocyte validation, GSH cotransport stoichiometry analysis, EHBR rat in vivo\",\n      \"pmids\": [\"16611857\", \"16501004\", \"16686371\", \"16877380\", \"17496208\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Bidirectional/export function shown only in oocytes\", \"GSH cotransport not validated in native membrane\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating selective transport of paclitaxel and active uptake of the toxin microcystin-LR linked OATP1B3 both to chemotherapeutic disposition and to toxin-mediated cell death signalling.\",\n      \"evidence\": \"Oocyte transporter panel for paclitaxel; HEK293 microcystin-LR uptake with PP2A/MAPK pathway and apoptosis readouts\",\n      \"pmids\": [\"17186002\", \"17369605\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Paclitaxel SNP associations negative in patients\", \"Microcystin downstream signalling specific to overexpression model\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Testosterone transport and its impairment by a common haplotype, plus a transport-dependent antiapoptotic effect in p53-wildtype cancer cells, connected OATP1B3 to hormone handling and chemoresistance.\",\n      \"evidence\": \"Cos-7 WT vs variant testosterone transport; colorectal cancer overexpression with transport-dead G583E control and p53 reporter/target analysis\",\n      \"pmids\": [\"18519758\", \"19074900\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking transport to p53 suppression not defined\", \"Haplotype effect not confirmed in vivo here\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Mapping substrate specificity to TM1/TM10/ECL6 and confirming Rotor syndrome via transgenic mouse rescue established both the structural logic of recognition and the in vivo physiological role in bilirubin reuptake.\",\n      \"evidence\": \"Chimeric/mutant transporter library with gain-of-function CCK-8 transport; Rotor family genetics with Oatp1a/1b-null and OATP1B3-transgenic rescue mice\",\n      \"pmids\": [\"22352740\", \"22232210\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of the transporter\", \"Substrate determinants mapped only for CCK-8\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Characterizing the cancer-type variant lacking the first 28 N-terminal residues as cytoplasmic and transport-impaired set up a distinct, non-canonical role for OATP1B3 in tumors.\",\n      \"evidence\": \"RT-PCR variant identification, subcellular fractionation, CCK-8 transport, proteasome inhibitor treatment in HEK293T\",\n      \"pmids\": [\"23215050\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Function of cytoplasmic variant not yet defined at this stage\", \"Truncation origin (splicing) mechanism not detailed here\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identifying Wnt/β-catenin and HIF-1α as cancer-context inducers and a sorafenib-glucuronide substrate role expanded the regulatory and pharmacologic picture in tumors.\",\n      \"evidence\": \"LiCl Wnt activation + HCC correlation; HIF-1α HRE reporter/EMSA/siRNA on cancer-specific promoter; HEK293 transport + Oatp1b2-null/transgenic mouse PK for sorafenib-glucuronide\",\n      \"pmids\": [\"24946283\", \"23924606\", \"23340295\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Wnt-to-promoter signalling steps not fully traced\", \"Cancer-specific vs liver-type promoter usage requires further dissection\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating PKC-mediated phosphorylation that suppresses activity without altering surface expression revealed acute post-translational control of transport function.\",\n      \"evidence\": \"Sandwich-cultured human hepatocytes, surface biotinylation, anti-phospho IP, CCK-8 assay, PKC inhibitor BIM I\",\n      \"pmids\": [\"25200870\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific phosphorylated residues not mapped\", \"Physiological trigger of PKC regulation unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showing β-islet expression and glibenclamide transport that enhances insulinotropic effect extended OATP1B3 function beyond liver to tissue-level drug action.\",\n      \"evidence\": \"MDCKII transport, CCK-8 inhibition, MIN6 overexpression with insulin secretion assay\",\n      \"pmids\": [\"24150606\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous β-cell expression level/relevance not quantified\", \"Single rodent β-cell model\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Bidirectional manipulation in prostate cancer models established that loss of SLCO1B3 reduces intratumoural taxane levels and drives resistance.\",\n      \"evidence\": \"PDX and PC346C models, siRNA knockdown and overexpression, [14C]-docetaxel/cabazitaxel uptake and cytotoxicity\",\n      \"pmids\": [\"27537383\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Regulatory cause of expression loss in resistant tumors not defined here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defining the N-terminal 12-28 region as required for membrane trafficking and quantifying testosterone uptake in vivo linked transporter localization, androgen disposition, and prostate cancer biology.\",\n      \"evidence\": \"N-terminal truncation/fusion mutants with fractionation in three cell lines; inducible cell kinetics and Slco1b2-/-/hSLCO1B3 knock-in mouse testosterone PK; CRPC siRNA\",\n      \"pmids\": [\"28216016\", \"28389619\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trafficking machinery recognizing the N-terminus not identified\", \"Mechanism of CRPC upregulation not resolved here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrating hetero-oligomerization with OCT1, OATP1B1, and NTCP that reciprocally alters membrane expression and turnover revealed transporter-transporter interplay as a functional regulator.\",\n      \"evidence\": \"Co-IP from human hepatocytes, proximity ligation in liver sections, surface biotinylation, CCK-8 transport, OCT1 knockdown\",\n      \"pmids\": [\"32482756\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Oligomer interface/stoichiometry not structurally defined\", \"Physiological extent of regulation in vivo unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying miR-579-3p as a 3'UTR-binding repressor whose abiraterone-induced downregulation upregulates SLCO1B3 added a post-transcriptional layer relevant to prostate cancer therapy.\",\n      \"evidence\": \"qPCR, NanoString miRNA profiling, dual luciferase 3'UTR reporter, 22Rv1 xenograft\",\n      \"pmids\": [\"34031488\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream control of miR-579-3p by abiraterone not fully mechanistic\", \"Clinical relevance to drug exposure untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Establishing that the cytoplasmic cancer variant binds IGF2BP2 to stabilize metabolic mRNAs assigned Ct-OATP1B3 a transport-independent moonlighting function driving cancer metabolic reprogramming and invasion.\",\n      \"evidence\": \"Co-IP, RNA-binding pulldown, mRNA stability and Seahorse metabolic assays, lamellipodia imaging, in vivo metastasis xenograft, siRNA\",\n      \"pmids\": [\"35717493\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect binding to CPT1A/NDUFA2 transcripts not resolved\", \"Generality beyond ovarian cancer unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A high-resolution structure defining the transport mechanism, ion coupling, and the molecular basis of multispecific substrate recognition across the full substrate range remains unestablished.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No experimental atomic structure in the corpus\", \"Specificity determinants mapped only for CCK-8\", \"Coupling ions/driving force not fully defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 2, 6, 7, 9, 10, 12, 14, 26]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0, 2, 16]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [29]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 25]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [18, 25, 29]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 6, 16]},\n      {\"term_id\": \"R-HSA-9748784\", \"supporting_discovery_ids\": [3, 7, 11, 12, 20, 24]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 16, 29]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SLCO1B1\", \"SLC22A1\", \"SLC10A1\", \"ABCC2\", \"IGF2BP2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}