{"gene":"SLCO1B1","run_date":"2026-06-10T07:46:35","timeline":{"discoveries":[{"year":2000,"finding":"OATP1B1 (SLC21A6) mediates high-affinity hepatic uptake of bilirubin and its glucuronate conjugates; HEK293 cells stably expressing recombinant OATP1B1 showed uptake of monoglucuronosyl bilirubin, bisglucuronosyl bilirubin, and sulfobromophthalein with Km values of 0.10, 0.28, and 0.14 µM respectively; transport of unconjugated bilirubin from albumin was also demonstrated and was not mediated by OATP8.","method":"Stable transfection of HEK293 cells with recombinant OATP1B1; radiolabeled substrate uptake assays; kinetic analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with kinetic characterization in stably transfected cells, replicated with multiple substrates","pmids":["11134001"],"is_preprint":false},{"year":2001,"finding":"OATP1B1 (SLC21A6) is localized to the basolateral (sinusoidal) membrane of human hepatocytes and its liver-specific expression is driven by the hepatocyte nuclear factor 1 alpha (HNF1α) binding to a functional element in the minimal promoter; mutation of the HNF1 site abolished promoter function.","method":"DNase I footprint analysis, electrophoretic mobility shift assay (EMSA), reporter gene assays with HNF1α co-expression in HepG2, Huh7, and HeLa cells; promoter deletion constructs","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (footprinting, EMSA, reporter assays, mutagenesis) in a single rigorous study","pmids":["11483603"],"is_preprint":false},{"year":2001,"finding":"OATP1B1 and MRP2 together mediate vectorial (basolateral-to-apical) transcellular transport of organic anions including 17β-estradiol 17β-D-glucuronide, pravastatin, and leukotriene C4 across a double-transfected MDCK II cell monolayer; Km values for E2-17βG and pravastatin for basal-to-apical flux were 27.9 and 24.3 µM respectively.","method":"Double-transfected MDCK II cell monolayer expressing OATP1B1 (basal) and MRP2 (apical); directional flux assays with radiolabeled substrates","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted vectorial transport in a polarized double-transfectant system with multiple substrates and kinetic characterization","pmids":["11748225"],"is_preprint":false},{"year":2002,"finding":"The naturally occurring OATP1B1 mutation L193R (SLC21A6) causes intracellular retention of the protein and abolishes organic anion transport; the mutation impairs protein maturation. In contrast, polymorphic variants N130D (P155T) were sorted correctly to the lateral membrane but showed altered transport for cholyltaurine and 17β-glucuronosyl estradiol.","method":"Stably transfected MDCK II cells with mutant SLC21A6 constructs; immunofluorescence microscopy for localization; radiolabeled uptake assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — site-directed mutagenesis, cellular localization by immunofluorescence, and functional transport assays in a single study","pmids":["12196548"],"is_preprint":false},{"year":2002,"finding":"Functional analysis in HEK293 cells of OATP1B1 alleles showed that the OATP1B1*15 variant (N130D + V174A combined) has a normalized Vmax for estrone-3-sulfate uptake reduced to less than 30% of wild-type, while the individual *1b (N130D) and *5 (V174A) variants did not significantly alter Km or corrected Vmax.","method":"Stably transfected HEK293 cells expressing OATP1B1 alleles; radiolabeled estrone-3-sulfate uptake kinetics; Western blot normalization of Vmax","journal":"The Journal of pharmacology and experimental therapeutics","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro transport reconstitution with multiple alleles, protein-level normalization, kinetic analysis","pmids":["12130747"],"is_preprint":false},{"year":2003,"finding":"OATP1B1 (OATP-C, SLC21A6) is the major hepatic uptake transporter for rifampin; HeLa cells expressing OATP-C showed greater affinity and capacity for rifampin transport than OATP8. OATP-C allelic variants had markedly decreased rifampin transport activity. OATP-C expression potentiated PXR reporter gene activity by increasing intracellular rifampin retention.","method":"Transient expression of OATP-C and OATP8 in HeLa cells; radiolabeled rifampin uptake assays; cell-based PXR transactivation reporter assay","journal":"The Journal of pharmacology and experimental therapeutics","confidence":"High","confidence_rationale":"Tier 1 / Strong — functional transport reconstitution combined with reporter gene transactivation assay, multiple alleles tested","pmids":["12490595"],"is_preprint":false},{"year":2003,"finding":"OATP1B1 (OATP-C) polymorphisms, particularly the T521C (Val174Ala) variant in the *15 allele, are associated with reduced non-renal clearance of pravastatin in vivo; subjects homozygous for *15 showed drastically reduced nonrenal clearance compared to *1b/*1b subjects.","method":"Clinical pharmacokinetic study with pravastatin as probe drug in 23 healthy volunteers genotyped for OATP-C polymorphisms; plasma/urine pharmacokinetic analysis","journal":"Clinical pharmacology and therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — controlled clinical PK study with genotype stratification, single lab, moderate sample size","pmids":["12811365"],"is_preprint":false},{"year":2003,"finding":"OATP-C (SLC21A6) mRNA is detectable only in human liver and not in human placenta at term, while OATP-8 and OATP-A are expressed in placenta. Xenopus oocytes injected with OATP-C mRNA transported unconjugated bilirubin (UCB) with higher affinity than OATP-8; Km for UCB transport was lower for OATP-C than OATP-8.","method":"Real-time RT-PCR for tissue distribution; Xenopus laevis oocyte expression system with radiolabeled substrate transport assays; kinetic analysis","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution in oocytes with kinetics, single lab","pmids":["12568656"],"is_preprint":false},{"year":2003,"finding":"SLC21A6 (OATP1B1) is not sufficient for bilirubin transport: stably transfected HeLa and HEK293 cells expressing OATP2 showed substantial sulfobromophthalein uptake but no significant increase in bilirubin uptake compared to uninduced controls, challenging the proposed role of OATP1B1 as a bilirubin transporter.","method":"Inducible stable transfection of HeLa cells and HEK293 cells with OATP2; radiolabeled bilirubin and sulfobromophthalein uptake assays; immunoblot confirmation of protein expression","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — rigorous in vitro reconstitution with negative result replicated in two cell lines; contradicts PMID 11134001","pmids":["12670950"],"is_preprint":false},{"year":2003,"finding":"SLC21A6 (OATP1B1) and SLC21A8 (OATP8) are both localized to the basolateral membrane of human hepatocytes, as established by immunofluorescence microscopy and immunoprecipitation with newly generated monoclonal antibodies. Both proteins are differentially expressed in hepatocellular carcinoma.","method":"Generation and characterization of monoclonal antibodies; immunoblot, immunoprecipitation, immunofluorescence microscopy in human liver and HCC samples","journal":"Laboratory investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by immunofluorescence with validated antibodies, confirmed in human tissue","pmids":["12695556"],"is_preprint":false},{"year":2004,"finding":"Gemfibrozil and its glucuronide metabolite (GEM-1-O-glu) inhibit OATP1B1 (OATP2)-mediated uptake of cerivastatin with IC50 values of 72 and 24 µM respectively in OATP2-expressing cells; both also inhibited CYP2C8-mediated metabolism, with GEM-1-O-glu being the primary driver of the clinical drug-drug interaction between cerivastatin and gemfibrozil.","method":"OATP2-expressing cell uptake inhibition assays with radiolabeled cerivastatin; CYP2C8 inhibition assays in P450 expression systems","journal":"The Journal of pharmacology and experimental therapeutics","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with inhibition kinetics for both transport and metabolism, multiple compounds tested","pmids":["15194707"],"is_preprint":false},{"year":2004,"finding":"Functional analysis of OATP1B1 SNP variants in stably transfected HEK293 cells showed that OATP1B1*15 (N130D + V174A) has normalized Vmax reduced to less than 30% of wild-type *1a; *1b (N130D alone) and *5 (V174A alone) show similar transport activity to wild-type. All variants are predominantly localized on the cell surface.","method":"Stably transfected HEK293 cells; uptake kinetics of radiolabeled E2-17βG; Western blot for protein expression normalization; immunofluorescence for subcellular localization","journal":"Pharmacogenetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with kinetics, protein normalization, localization; multiple orthogonal methods","pmids":["15564882"],"is_preprint":false},{"year":2004,"finding":"OATP1B1 together with MRP2 mediates transcellular transport of rifampin across LLC-PK1 cell monolayers co-expressing both transporters; directional transport was demonstrated for the first time for rifampin through this transporter pair.","method":"Porcine LLC-PK1 cells stably co-expressing OATP1B1 and MRP2; directional transport assays across monolayers","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro transcellular transport reconstitution, single lab, single study","pmids":["15652233"],"is_preprint":false},{"year":2005,"finding":"Multiple naturally occurring flavonoids inhibit OATP1B1-mediated transport of DHEAS in a concentration-dependent manner in OATP1B1-expressing HeLa cells; biochanin A is among the most potent inhibitors (IC50 ~11 µM) and acts via a noncompetitive mechanism (Ki ~10 µM). Biochanin A is not itself a substrate of OATP1B1.","method":"OATP1B1-expressing HeLa cells; radiolabeled DHEAS uptake inhibition assays; kinetic analysis of inhibition mechanism","journal":"Drug metabolism and disposition","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro uptake assays with inhibition kinetics in OATP1B1-expressing vs. negative cells, multiple compounds","pmids":["16081670"],"is_preprint":false},{"year":2006,"finding":"OATP1B1 mediates hepatic uptake of enalapril with a Km of ~262 µM in HEK293 cells; double-transfected MDCK II cells expressing OATP1B1 and MRP2 showed significantly higher sinusoidal-to-canalicular vectorial flux of enalapril, demonstrating the coupled role of these two transporters in hepatic enalapril disposition.","method":"HEK293 cells transfected with OATP1B1 or OATP1B3; radiolabeled enalapril uptake kinetics; double-transfected MDCK II cells with OATP1B1 and MRP2; Transwell directional flux assays","journal":"The Journal of pharmacology and experimental therapeutics","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with kinetics plus transcellular transport in polarized double-transfectant system","pmids":["16627748"],"is_preprint":false},{"year":2010,"finding":"OATP1B1 transcription is under dual nuclear receptor control: LXRα and FXR directly regulate OATP1B1 gene expression. Two functional FXR response elements and one LXRα response element were identified in the OATP1B1 promoter; direct receptor-promoter binding was confirmed by chromatin immunoprecipitation. LXRα or FXR agonists induced OATP1B1 mRNA in primary human hepatocytes, whereas PXR and CAR agonists did not.","method":"Promoter deletion/reporter gene assays; chromatin immunoprecipitation (ChIP); siRNA knockdown; primary human hepatocyte treatment with nuclear receptor ligands","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (reporter assays, ChIP, primary hepatocytes, siRNA) in a single comprehensive study","pmids":["20827719"],"is_preprint":false},{"year":2010,"finding":"Maraviroc is a substrate of OATP1B1 with a Km of 33.9 µM, as demonstrated in a Xenopus laevis oocyte expression system. The SLCO1B1 521T>C polymorphism was associated with higher maraviroc trough plasma concentrations in HIV-infected patients.","method":"Xenopus laevis oocyte heterologous expression system; LC-MS/MS quantification; clinical pharmacokinetic analysis","journal":"Pharmacogenetics and genomics","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro transport reconstitution in oocytes with kinetic parameters, supported by clinical PK data","pmids":["21217360"],"is_preprint":false},{"year":2010,"finding":"Flavopiridol and its glucuronide metabolite are substrates of OATP1B1, as demonstrated in transiently transfected HEK-293 and MDCK-II cells. SLCO1B1 polymorphisms were associated with flavopiridol pharmacokinetics in a population pharmacokinetic model.","method":"Transient transfection of HEK-293 and MDCK-II cells with SLCO1B1; uptake assays; population pharmacokinetic modeling from clinical data","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro transport reconstitution validated by clinical PK data, two cell line systems","pmids":["21072184"],"is_preprint":false},{"year":2013,"finding":"OATP1B1 transports sorafenib-glucuronide (10.6-fold over control) in HEK293 cells stably transfected with OATP1B1; plasma levels of sorafenib-glucuronide were increased >8-fold in Oatp1b2-knockout mice. Introduction of human OATP1B1 in knockout mice partially restored clearance of sorafenib-glucuronide.","method":"Stably transfected HEK293 cells with OATP1B1; radiolabeled/LC-MS uptake assays; Oatp1b2-knockout and humanized OATP1B1-transgenic mice pharmacokinetic studies","journal":"Clinical cancer research","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution combined with in vivo knockout and humanized transgenic mouse models","pmids":["23340295"],"is_preprint":false},{"year":2013,"finding":"In vivo studies using oatp1a/1b-knockout and liver-specific OATP1B1-humanized mice established that OATP1B1 mediates hepatic uptake and clearance of statins (pravastatin, atorvastatin, simvastatin); oatp1a/1b-knockout mice showed up to 115-fold increased oral drug exposure and up to 196-fold lower hepatic drug distribution, partially restored by OATP1B1 knockin.","method":"Oatp1a/1b-knockout and liver-specific OATP1B1-humanized transgenic mice; pharmacokinetic studies with IV and oral administration; quantitative proteomics","journal":"Drug metabolism and disposition","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout and humanized transgenic mouse models with multiple statins, replicated across genotypes","pmids":["24194513"],"is_preprint":false},{"year":2014,"finding":"OATP1B1 mediates hepatic uptake of docetaxel in vivo; liver-specific expression of OATP1B1 in Oatp1a/1b-knockout mice nearly completely rescued the increased plasma levels of docetaxel seen in knockout mice after IV administration.","method":"Oatp1a/1b-knockout mice and liver-specific OATP1B1-humanized transgenic mice; in vivo pharmacokinetic studies with docetaxel; liver-to-plasma ratio measurements","journal":"International journal of cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo functional rescue experiment in humanized transgenic mice, multiple human OATP isoforms tested","pmids":["24825069"],"is_preprint":false},{"year":2014,"finding":"OATP1B1 mediates uptake of nilotinib (Km 10.14 µM) and vandetanib (Km 2.72 µM) in CHO cells transfected with OATP1B1; canertinib, erlotinib, and pazopanib did not show substrate specificity toward OATP1B1.","method":"CHO cells transfected with OATP1B1; concentration-dependent cellular accumulation assays; Michaelis-Menten kinetic analysis","journal":"Drug metabolism and drug interactions","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro kinetic characterization, single lab, single method","pmids":["24643910"],"is_preprint":false},{"year":2017,"finding":"OATP1B1 function is regulated by tyrosine kinase-mediated phosphorylation at tyrosine residue 645. Inhibition of OATP1B1 by tyrosine kinase inhibitors (TKIs) such as nilotinib is predominantly noncompetitive and is associated with reduced phosphorylation at Y645. The Src kinase LYN was identified as a regulator of OATP1B1 activity using a siRNA kinome screen (779 kinases).","method":"Overexpressing HEK293 cells and primary hepatocytes; TKI transport inhibition assays; LC/MS-MS phosphoproteomics; siRNA kinome screen; in vivo rosuvastatin PK with nilotinib in mice","journal":"Clinical cancer research","confidence":"High","confidence_rationale":"Tier 1 / Strong — phosphoproteomics identification of modification site, siRNA functional screen, mutagenesis validation, in vivo confirmation; multiple orthogonal methods","pmids":["33664059"],"is_preprint":false},{"year":2017,"finding":"OATP1B1 function is affected by SLCO1B1 variants altering protein folding and degradation; deep mutational scanning of 137 SLCO1B1 missense variants identified 6 variants with <25% and 12 with ~50% of wild-type protein expression, with functional validation by transporter assays.","method":"Deep mutational scanning (DMS) using landing pad cell-based system with GFP fusion and FACS; next-generation sequencing; functional transport validation assays","journal":"Drug metabolism and disposition","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — high-throughput screening with functional validation, single lab, novel approach with some caveats for membrane proteins noted by authors","pmids":["33658230"],"is_preprint":false},{"year":2019,"finding":"Preincubation with rifampicin and dasatinib potentiates inhibitory effects on OATP1B1-mediated transport by reducing Ki values (rifampicin 3-fold, dasatinib 2.1-fold for OATP1B1), without affecting plasma membrane localization of GFP-tagged OATP1B1 in HEK293 cells, as confirmed by time-lapse confocal microscopy.","method":"HEK293 stable cell lines with GFP-OATP1B1; transport inhibition assays with preincubation; Ki determination; confocal microscopy; human sandwich-cultured hepatocytes","journal":"Journal of pharmaceutical sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assays with mechanistic Ki, localization confirmed by confocal microscopy, multiple cell systems","pmids":["28373111"],"is_preprint":false},{"year":2020,"finding":"Coexpression of OATP1B3 with OATP1B1 in HEK293 cells increases OATP1B3 plasma membrane expression while decreasing its apparent turnover rate, suggesting hetero-oligomerization modulates OATP1B3 function; this implies that single-transporter overexpression systems may over- or underestimate OATP1B1-related function.","method":"Co-immunoprecipitation; proximity ligation assay in HEK293 cells and human liver sections; membrane expression quantification; cholecystokinin-8 uptake assays","journal":"Drug metabolism and disposition","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal protein interaction demonstrated by Co-IP and PLA, functional consequences measured, confirmed in human liver tissue","pmids":["32482756"],"is_preprint":false},{"year":2020,"finding":"Berberine promotes OATP1B1 expression and rosuvastatin uptake in HepG2 cells by inducing nuclear translocation and activation of FXR and LXRα; siRNA silencing of FXR or LXRα attenuated berberine-induced OATP1B1 expression.","method":"HepG2 cell treatment with berberine; rosuvastatin uptake assay; dual-luciferase reporter assay; siRNA knockdown of FXR and LXRα; Western blot of cytoplasm/nuclear fractions","journal":"Frontiers in pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, siRNA, subcellular fractionation, functional transport), single lab","pmids":["32292349"],"is_preprint":false},{"year":2022,"finding":"Functional analysis of rare SLCO1B1 variants in HEK293 cells showed that R57Q impairs both DCF and rosuvastatin transport without reducing protein expression, while R253Q reduces DCF uptake and increases rosuvastatin Km. N130D and N151S do not alter activity but increase protein expression. QTAP proteomics confirmed OATP1B1 protein abundance differences among variants.","method":"HEK293 cells overexpressing SLCO1B1 variants; uptake assays with DCF and rosuvastatin; LC-MS/MS-based QTAP proteomics; pharmacokinetic simulations","journal":"European journal of pharmaceutical sciences","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro transport reconstitution with multiple substrates and protein quantification by proteomics, single lab","pmids":["35752377"],"is_preprint":false}],"current_model":"OATP1B1 (SLCO1B1) is a sodium-independent uptake transporter expressed exclusively at the basolateral (sinusoidal) membrane of human hepatocytes, where its liver-specific expression is driven by HNF1α (and modulated by FXR and LXRα); it mediates high-affinity hepatic uptake of bile acids, bilirubin conjugates, statins, rifampin, and numerous drugs, and works in concert with canalicular efflux transporters (especially MRP2) to achieve vectorial hepatobiliary transport; its activity is regulated post-translationally by LYN-mediated phosphorylation at tyrosine 645, and common loss-of-function variants (notably *5/V174A and *15/N130D+V174A) reduce transport capacity by impairing protein folding or intrinsic activity, leading to increased systemic drug exposure and statin-induced myopathy risk."},"narrative":{"mechanistic_narrative":"SLCO1B1 encodes OATP1B1, a sodium-independent organic anion uptake transporter localized to the basolateral (sinusoidal) membrane of human hepatocytes that mediates hepatic clearance of bile acid conjugates, drugs, and their metabolites [PMID:12695556, PMID:12196548]. It transports a broad range of organic anions and pharmaceuticals, including sulfobromophthalein, bilirubin conjugates, statins (pravastatin), rifampin, enalapril, maraviroc, docetaxel, and glucuronide metabolites of sorafenib and gemfibrozil [PMID:11134001, PMID:11748225, PMID:12490595, PMID:16627748], with in vivo knockout and liver-specific humanized mouse models confirming its dominant role in hepatic uptake and systemic clearance of statins and chemotherapeutics [PMID:24194513, PMID:24825069, PMID:23340295]. OATP1B1 achieves vectorial hepatobiliary transport by working in series with the canalicular efflux pump MRP2, as reconstituted in double-transfected polarized monolayers for estradiol glucuronide, pravastatin, rifampin, and enalapril [PMID:11748225, PMID:15652233, PMID:16627748]. Its liver-restricted expression is driven by HNF1α binding to the minimal promoter [PMID:11483603] and is further controlled by direct transcriptional regulation through FXR and LXRα response elements [PMID:20827719, PMID:32292349], while post-translationally its activity depends on LYN/Src-family tyrosine kinase phosphorylation at Tyr645, the site through which tyrosine kinase inhibitors noncompetitively suppress transport [PMID:33664059]. Common and rare missense variants modulate function through distinct mechanisms: L193R causes intracellular retention and abolishes maturation, the *15 haplotype (N130D+V174A) reduces normalized Vmax to under 30% of wild-type while remaining surface-localized, and folding/expression effects across the variant landscape reduce protein abundance — changes that lower hepatic clearance and increase systemic drug exposure in vivo [PMID:12196548, PMID:15564882, PMID:33658230, PMID:12811365].","teleology":[{"year":2000,"claim":"Established OATP1B1 as a high-affinity hepatic uptake transporter for endogenous organic anions, defining its substrate class biochemically.","evidence":"Radiolabeled uptake kinetics for bilirubin conjugates and sulfobromophthalein in stably transfected HEK293 cells","pmids":["11134001"],"confidence":"High","gaps":["Bilirubin transport role was later challenged","Did not address membrane polarity or in vivo relevance"]},{"year":2001,"claim":"Resolved where the transporter acts and why it is liver-specific, anchoring OATP1B1 to the sinusoidal membrane and identifying HNF1α as the driver of its tissue-restricted expression.","evidence":"Immunolocalization in human liver plus DNase footprinting, EMSA, and reporter assays in hepatic cell lines","pmids":["11483603"],"confidence":"High","gaps":["Did not address additional transcriptional regulators identified later","No post-translational regulation examined"]},{"year":2001,"claim":"Demonstrated that OATP1B1 functions as the uptake arm of a coupled vectorial transport system, working with MRP2 to move organic anions basal-to-apical across hepatocytes.","evidence":"Directional flux assays in OATP1B1/MRP2 double-transfected MDCK II monolayers","pmids":["11748225"],"confidence":"High","gaps":["Reconstituted in heterologous epithelium, not native hepatocytes","Stoichiometry of coupling not defined"]},{"year":2002,"claim":"Distinguished folding/trafficking defects from intrinsic activity defects among variants, showing L193R is retained intracellularly while *15 (N130D+V174A) is surface-localized but functionally impaired.","evidence":"Site-directed mutagenesis, immunofluorescence localization, and uptake kinetics with protein normalization in MDCK II and HEK293 cells","pmids":["12196548","12130747","15564882"],"confidence":"High","gaps":["Mechanism by which V174A lowers turnover not resolved at structural level","Single-variant heterologous systems"]},{"year":2003,"claim":"Extended the substrate range to clinically important drugs and linked variant transport defects to altered drug disposition in humans, establishing pharmacogenetic relevance.","evidence":"Rifampin uptake and PXR transactivation assays in HeLa cells; pravastatin pharmacokinetic study in genotyped volunteers","pmids":["12490595","12811365"],"confidence":"Medium","gaps":["Clinical PK study was modest in size, single lab","In vivo causality not isolated from other clearance routes"]},{"year":2003,"claim":"Challenged the bilirubin-transporter assignment, with replicated negative uptake data questioning whether OATP1B1 is sufficient for bilirubin transport.","evidence":"Inducible stable transfection and bilirubin/BSP uptake assays in two cell lines","pmids":["12670950"],"confidence":"Medium","gaps":["Discrepancy with earlier positive bilirubin findings unresolved","Possible differences in substrate presentation or cofactors not examined"]},{"year":2004,"claim":"Defined the mechanistic basis of a clinical drug-drug interaction, showing a glucuronide metabolite inhibits OATP1B1-mediated statin uptake.","evidence":"Cerivastatin uptake inhibition by gemfibrozil and its glucuronide in OATP2-expressing cells, with parallel CYP2C8 inhibition","pmids":["15194707"],"confidence":"High","gaps":["Relative contribution of transport vs metabolism inhibition in vivo not partitioned in this study"]},{"year":2010,"claim":"Expanded transcriptional control beyond HNF1α, identifying FXR and LXRα as direct nuclear-receptor regulators of OATP1B1 expression.","evidence":"Promoter reporter assays, ChIP, siRNA, and ligand treatment of primary human hepatocytes","pmids":["20827719"],"confidence":"High","gaps":["Interplay between HNF1α and nuclear-receptor inputs not integrated","Physiological stimuli driving these receptors in vivo not defined here"]},{"year":2013,"claim":"Provided in vivo proof that OATP1B1 governs hepatic uptake and systemic clearance of statins and drug glucuronides, moving beyond cell-based inference.","evidence":"Oatp1a/1b-knockout and liver-specific OATP1B1-humanized mice with statin and sorafenib-glucuronide pharmacokinetics","pmids":["24194513","23340295"],"confidence":"High","gaps":["Mouse humanization is partial; quantitative scaling to human uncertain","Contribution of other OATP isoforms not fully separated"]},{"year":2017,"claim":"Identified post-translational kinase control of transporter activity, mapping LYN-mediated phosphorylation at Tyr645 as a regulatory node exploited by tyrosine kinase inhibitors.","evidence":"Phosphoproteomics, siRNA kinome screen, mutagenesis, and in vivo rosuvastatin PK with nilotinib","pmids":["33664059"],"confidence":"High","gaps":["Upstream signals activating LYN toward OATP1B1 unknown","How Y645 phosphorylation alters transport mechanistically not resolved"]},{"year":2020,"claim":"Revealed that OATP1B1 hetero-oligomerizes with OATP1B3, modulating membrane expression and turnover and complicating single-transporter functional estimates.","evidence":"Co-immunoprecipitation, proximity ligation assay in cells and human liver, and uptake assays","pmids":["32482756"],"confidence":"Medium","gaps":["Functional impact on OATP1B1 substrates specifically not quantified","Stoichiometry and physiological extent of oligomerization unclear"]},{"year":2022,"claim":"Systematically separated folding/expression effects from intrinsic activity effects across rare variants, refining the genotype-to-function map.","evidence":"Deep mutational scanning and variant uptake assays with QTAP proteomics in HEK293 cells","pmids":["33658230","35752377"],"confidence":"Medium","gaps":["High-throughput membrane-protein assays carry expression-system caveats","Clinical translation of many rare variants untested"]},{"year":null,"claim":"How transcriptional (HNF1α/FXR/LXRα), post-translational (LYN/Y645), and oligomerization inputs are integrated to set hepatic OATP1B1 transport capacity in vivo remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified regulatory model connecting transcription, phosphorylation, and oligomerization","Structural basis of substrate recognition and transport cycle not established in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,2,5,14,16,18,19]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,9,11,24]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,2,19]},{"term_id":"R-HSA-9748784","term_label":"Drug ADME","supporting_discovery_ids":[5,19,18]}],"complexes":[],"partners":["MRP2","ABCC2","SLCO1B3","LYN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y6L6","full_name":"Solute carrier organic anion transporter family member 1B1","aliases":["Liver-specific organic anion transporter 1","LST-1","OATP-C","Organic anion transporter SLC21A6","Sodium-independent organic anion-transporting polypeptide 2","OATP-2","Solute carrier family 21 member 6"],"length_aa":691,"mass_kda":76.4,"function":"Mediates the Na(+)-independent uptake of organic anions (PubMed:10358072, PubMed:15159445, PubMed:17412826). Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (dehydroepiandrosterone 3-sulfate, 17-beta-glucuronosyl estradiol, and estrone 3-sulfate), as well as eicosanoids (prostaglandin E2, thromboxane B2, leukotriene C4, and leukotriene E4), and thyroid hormones (T4/L-thyroxine, and T3/3,3',5'-triiodo-L-thyronine) (PubMed:10358072, PubMed:10601278, PubMed:10873595, PubMed:11159893, PubMed:12196548, PubMed:12568656, PubMed:15159445, PubMed:15970799, PubMed:16627748, PubMed:17412826, PubMed:19129463, PubMed:26979622). Can take up bilirubin glucuronides from plasma into the liver, contributing to the detoxification-enhancing liver-blood shuttling loop (PubMed:22232210). Involved in the clearance of endogenous and exogenous substrates from the liver (PubMed:10358072, PubMed:10601278). 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 pravastatin and pitavastatin, a clinically important class of hypolipidemic drugs (PubMed:10601278, PubMed:15159445, PubMed:15970799). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drug methotrexate (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). Shows a pH-sensitive substrate specificity towards prostaglandin E2 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). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463)","subcellular_location":"Basolateral cell membrane; Basal cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9Y6L6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLCO1B1","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/SLCO1B1","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":"619662","title":"CHOLESTASIS, PROGRESSIVE FAMILIAL INTRAHEPATIC, 8; PFIC8","url":"https://www.omim.org/entry/619662"},{"mim_id":"613389","title":"SOLUTE CARRIER ORGANIC ANION TRANSPORTER FAMILY, MEMBER 1C1; SLCO1C1","url":"https://www.omim.org/entry/613389"},{"mim_id":"611278","title":"KINESIN FAMILY MEMBER 12; KIF12","url":"https://www.omim.org/entry/611278"},{"mim_id":"605495","title":"SOLUTE CARRIER ORGANIC ANION TRANSPORTER FAMILY, MEMBER 1B3; SLCO1B3","url":"https://www.omim.org/entry/605495"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"liver","ntpm":502.3}],"url":"https://www.proteinatlas.org/search/SLCO1B1"},"hgnc":{"alias_symbol":["OATP-C","LST-1","OATP1B1"],"prev_symbol":["SLC21A6"]},"alphafold":{"accession":"Q9Y6L6","domains":[{"cath_id":"1.20.1250.20","chopping":"20-124_168-284","consensus_level":"high","plddt":90.1062,"start":20,"end":284},{"cath_id":"1.20.1250.20","chopping":"329-432_529-646","consensus_level":"high","plddt":92.1763,"start":329,"end":646},{"cath_id":"-","chopping":"435-525","consensus_level":"medium","plddt":83.0109,"start":435,"end":525}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6L6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6L6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6L6-F1-predicted_aligned_error_v6.png","plddt_mean":80.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLCO1B1","jax_strain_url":"https://www.jax.org/strain/search?query=SLCO1B1"},"sequence":{"accession":"Q9Y6L6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y6L6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y6L6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6L6"}},"corpus_meta":[{"pmid":"18650507","id":"PMC_18650507","title":"SLCO1B1 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OATP1B3.","date":"2015","source":"European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/25603031","citation_count":15,"is_preprint":false},{"pmid":"19122343","id":"PMC_19122343","title":"Genetic variations of the SLCO1B1 gene in the Chinese, Malay and Indian populations of Singapore.","date":"2008","source":"Drug metabolism and pharmacokinetics","url":"https://pubmed.ncbi.nlm.nih.gov/19122343","citation_count":15,"is_preprint":false},{"pmid":"32361904","id":"PMC_32361904","title":"Effects of ABCG2 and SLCO1B1 gene variants on inflammation markers in patients with hypercholesterolemia and diabetes mellitus treated with rosuvastatin.","date":"2020","source":"European journal of clinical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/32361904","citation_count":15,"is_preprint":false},{"pmid":"28049954","id":"PMC_28049954","title":"No Effect of SLCO1B1 and CYP3A4/5 Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Ticagrelor in Healthy Chinese Male Subjects.","date":"2017","source":"Biological & pharmaceutical bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/28049954","citation_count":15,"is_preprint":false},{"pmid":"25084202","id":"PMC_25084202","title":"Expression and activity of ABCG2, but not ABCB1 or OATP1B1, are associated with cholesterol levels: evidence from in vitro and in vivo experiments.","date":"2014","source":"Pharmacogenomics","url":"https://pubmed.ncbi.nlm.nih.gov/25084202","citation_count":15,"is_preprint":false},{"pmid":"37490620","id":"PMC_37490620","title":"Real-world pharmacogenetics of statin intolerance: effects of SLCO1B1, ABCG2 , and CYP2C9 variants.","date":"2023","source":"Pharmacogenetics and genomics","url":"https://pubmed.ncbi.nlm.nih.gov/37490620","citation_count":14,"is_preprint":false},{"pmid":"32166864","id":"PMC_32166864","title":"Effect of Rifampin-Mediated OATP1B1 and OATP1B3 Transporter Inhibition on the Pharmacokinetics of the P2Y12 Receptor Antagonist Selatogrel.","date":"2020","source":"Clinical and translational science","url":"https://pubmed.ncbi.nlm.nih.gov/32166864","citation_count":14,"is_preprint":false},{"pmid":"32292349","id":"PMC_32292349","title":"Berberine Promotes OATP1B1 Expression and Rosuvastatin Uptake by Inducing Nuclear Translocation of FXR and LXRα.","date":"2020","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/32292349","citation_count":13,"is_preprint":false},{"pmid":"37253618","id":"PMC_37253618","title":"A gene risk score using missense variants in SLCO1B1 is associated with earlier onset statin intolerance.","date":"2023","source":"European heart journal. Cardiovascular pharmacotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/37253618","citation_count":13,"is_preprint":false},{"pmid":"31737051","id":"PMC_31737051","title":"Combined Effects of UGT1A1 and SLCO1B1 Variants on Chinese Adult Mild Unconjugated Hyperbilirubinemia.","date":"2019","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31737051","citation_count":13,"is_preprint":false},{"pmid":"25932441","id":"PMC_25932441","title":"Meta-Analysis of the SLCO1B1 c.521T>C Variant Reveals Slight Influence on the Lipid-Lowering Efficacy of Statins.","date":"2015","source":"Annals of laboratory medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25932441","citation_count":12,"is_preprint":false},{"pmid":"25939871","id":"PMC_25939871","title":"Influence of SLCO1B1 polymorphism on maintenance therapy for childhood leukemia.","date":"2015","source":"Pediatrics international : official journal of the Japan Pediatric Society","url":"https://pubmed.ncbi.nlm.nih.gov/25939871","citation_count":12,"is_preprint":false},{"pmid":"19293444","id":"PMC_19293444","title":"Organic anion transporter protein (OATP1B1) encoded by SLCO1B1 gene polymorphism (388A>G) & susceptibility in gallstone disease.","date":"2009","source":"The Indian journal of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/19293444","citation_count":11,"is_preprint":false},{"pmid":"28975866","id":"PMC_28975866","title":"SLCO1A2, SLCO1B1 and SLCO2B1 polymorphisms influences chloroquine and primaquine treatment in Plasmodium vivax malaria.","date":"2017","source":"Pharmacogenomics","url":"https://pubmed.ncbi.nlm.nih.gov/28975866","citation_count":11,"is_preprint":false},{"pmid":"30368586","id":"PMC_30368586","title":"Associations among regorafenib concentrations, severe adverse reactions, and ABCG2 and OATP1B1 polymorphisms.","date":"2018","source":"Cancer chemotherapy and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30368586","citation_count":11,"is_preprint":false},{"pmid":"34423897","id":"PMC_34423897","title":"SLCO1B1 *15 allele is associated with methotrexate-induced nausea in pediatric patients with inflammatory bowel disease.","date":"2021","source":"Clinical and translational science","url":"https://pubmed.ncbi.nlm.nih.gov/34423897","citation_count":11,"is_preprint":false},{"pmid":"23850112","id":"PMC_23850112","title":"The impact of SLCO1B1 genetic polymorphisms on neonatal hyperbilirubinemia: a systematic review with meta-analysis.","date":"2013","source":"Jornal de pediatria","url":"https://pubmed.ncbi.nlm.nih.gov/23850112","citation_count":11,"is_preprint":false},{"pmid":"36811234","id":"PMC_36811234","title":"Mechanistic in vitro studies indicate that the clinical drug-drug interactions between protease inhibitors and rosuvastatin are driven by inhibition of intestinal BCRP and hepatic OATP1B1 with minimal contribution from OATP1B3, NTCP and OAT3.","date":"2023","source":"Pharmacology research & perspectives","url":"https://pubmed.ncbi.nlm.nih.gov/36811234","citation_count":11,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":61244,"output_tokens":7378,"usd":0.147201,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16345,"output_tokens":3773,"usd":0.088025,"stage2_stop_reason":"end_turn"},"total_usd":0.235226,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"OATP1B1 (SLC21A6) mediates high-affinity hepatic uptake of bilirubin and its glucuronate conjugates; HEK293 cells stably expressing recombinant OATP1B1 showed uptake of monoglucuronosyl bilirubin, bisglucuronosyl bilirubin, and sulfobromophthalein with Km values of 0.10, 0.28, and 0.14 µM respectively; transport of unconjugated bilirubin from albumin was also demonstrated and was not mediated by OATP8.\",\n      \"method\": \"Stable transfection of HEK293 cells with recombinant OATP1B1; radiolabeled substrate uptake assays; kinetic analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with kinetic characterization in stably transfected cells, replicated with multiple substrates\",\n      \"pmids\": [\"11134001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"OATP1B1 (SLC21A6) is localized to the basolateral (sinusoidal) membrane of human hepatocytes and its liver-specific expression is driven by the hepatocyte nuclear factor 1 alpha (HNF1α) binding to a functional element in the minimal promoter; mutation of the HNF1 site abolished promoter function.\",\n      \"method\": \"DNase I footprint analysis, electrophoretic mobility shift assay (EMSA), reporter gene assays with HNF1α co-expression in HepG2, Huh7, and HeLa cells; promoter deletion constructs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (footprinting, EMSA, reporter assays, mutagenesis) in a single rigorous study\",\n      \"pmids\": [\"11483603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"OATP1B1 and MRP2 together mediate vectorial (basolateral-to-apical) transcellular transport of organic anions including 17β-estradiol 17β-D-glucuronide, pravastatin, and leukotriene C4 across a double-transfected MDCK II cell monolayer; Km values for E2-17βG and pravastatin for basal-to-apical flux were 27.9 and 24.3 µM respectively.\",\n      \"method\": \"Double-transfected MDCK II cell monolayer expressing OATP1B1 (basal) and MRP2 (apical); directional flux assays with radiolabeled substrates\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted vectorial transport in a polarized double-transfectant system with multiple substrates and kinetic characterization\",\n      \"pmids\": [\"11748225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The naturally occurring OATP1B1 mutation L193R (SLC21A6) causes intracellular retention of the protein and abolishes organic anion transport; the mutation impairs protein maturation. In contrast, polymorphic variants N130D (P155T) were sorted correctly to the lateral membrane but showed altered transport for cholyltaurine and 17β-glucuronosyl estradiol.\",\n      \"method\": \"Stably transfected MDCK II cells with mutant SLC21A6 constructs; immunofluorescence microscopy for localization; radiolabeled uptake assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — site-directed mutagenesis, cellular localization by immunofluorescence, and functional transport assays in a single study\",\n      \"pmids\": [\"12196548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Functional analysis in HEK293 cells of OATP1B1 alleles showed that the OATP1B1*15 variant (N130D + V174A combined) has a normalized Vmax for estrone-3-sulfate uptake reduced to less than 30% of wild-type, while the individual *1b (N130D) and *5 (V174A) variants did not significantly alter Km or corrected Vmax.\",\n      \"method\": \"Stably transfected HEK293 cells expressing OATP1B1 alleles; radiolabeled estrone-3-sulfate uptake kinetics; Western blot normalization of Vmax\",\n      \"journal\": \"The Journal of pharmacology and experimental therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro transport reconstitution with multiple alleles, protein-level normalization, kinetic analysis\",\n      \"pmids\": [\"12130747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"OATP1B1 (OATP-C, SLC21A6) is the major hepatic uptake transporter for rifampin; HeLa cells expressing OATP-C showed greater affinity and capacity for rifampin transport than OATP8. OATP-C allelic variants had markedly decreased rifampin transport activity. OATP-C expression potentiated PXR reporter gene activity by increasing intracellular rifampin retention.\",\n      \"method\": \"Transient expression of OATP-C and OATP8 in HeLa cells; radiolabeled rifampin uptake assays; cell-based PXR transactivation reporter assay\",\n      \"journal\": \"The Journal of pharmacology and experimental therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — functional transport reconstitution combined with reporter gene transactivation assay, multiple alleles tested\",\n      \"pmids\": [\"12490595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"OATP1B1 (OATP-C) polymorphisms, particularly the T521C (Val174Ala) variant in the *15 allele, are associated with reduced non-renal clearance of pravastatin in vivo; subjects homozygous for *15 showed drastically reduced nonrenal clearance compared to *1b/*1b subjects.\",\n      \"method\": \"Clinical pharmacokinetic study with pravastatin as probe drug in 23 healthy volunteers genotyped for OATP-C polymorphisms; plasma/urine pharmacokinetic analysis\",\n      \"journal\": \"Clinical pharmacology and therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — controlled clinical PK study with genotype stratification, single lab, moderate sample size\",\n      \"pmids\": [\"12811365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"OATP-C (SLC21A6) mRNA is detectable only in human liver and not in human placenta at term, while OATP-8 and OATP-A are expressed in placenta. Xenopus oocytes injected with OATP-C mRNA transported unconjugated bilirubin (UCB) with higher affinity than OATP-8; Km for UCB transport was lower for OATP-C than OATP-8.\",\n      \"method\": \"Real-time RT-PCR for tissue distribution; Xenopus laevis oocyte expression system with radiolabeled substrate transport assays; kinetic analysis\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution in oocytes with kinetics, single lab\",\n      \"pmids\": [\"12568656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SLC21A6 (OATP1B1) is not sufficient for bilirubin transport: stably transfected HeLa and HEK293 cells expressing OATP2 showed substantial sulfobromophthalein uptake but no significant increase in bilirubin uptake compared to uninduced controls, challenging the proposed role of OATP1B1 as a bilirubin transporter.\",\n      \"method\": \"Inducible stable transfection of HeLa cells and HEK293 cells with OATP2; radiolabeled bilirubin and sulfobromophthalein uptake assays; immunoblot confirmation of protein expression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — rigorous in vitro reconstitution with negative result replicated in two cell lines; contradicts PMID 11134001\",\n      \"pmids\": [\"12670950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SLC21A6 (OATP1B1) and SLC21A8 (OATP8) are both localized to the basolateral membrane of human hepatocytes, as established by immunofluorescence microscopy and immunoprecipitation with newly generated monoclonal antibodies. Both proteins are differentially expressed in hepatocellular carcinoma.\",\n      \"method\": \"Generation and characterization of monoclonal antibodies; immunoblot, immunoprecipitation, immunofluorescence microscopy in human liver and HCC samples\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by immunofluorescence with validated antibodies, confirmed in human tissue\",\n      \"pmids\": [\"12695556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Gemfibrozil and its glucuronide metabolite (GEM-1-O-glu) inhibit OATP1B1 (OATP2)-mediated uptake of cerivastatin with IC50 values of 72 and 24 µM respectively in OATP2-expressing cells; both also inhibited CYP2C8-mediated metabolism, with GEM-1-O-glu being the primary driver of the clinical drug-drug interaction between cerivastatin and gemfibrozil.\",\n      \"method\": \"OATP2-expressing cell uptake inhibition assays with radiolabeled cerivastatin; CYP2C8 inhibition assays in P450 expression systems\",\n      \"journal\": \"The Journal of pharmacology and experimental therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with inhibition kinetics for both transport and metabolism, multiple compounds tested\",\n      \"pmids\": [\"15194707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Functional analysis of OATP1B1 SNP variants in stably transfected HEK293 cells showed that OATP1B1*15 (N130D + V174A) has normalized Vmax reduced to less than 30% of wild-type *1a; *1b (N130D alone) and *5 (V174A alone) show similar transport activity to wild-type. All variants are predominantly localized on the cell surface.\",\n      \"method\": \"Stably transfected HEK293 cells; uptake kinetics of radiolabeled E2-17βG; Western blot for protein expression normalization; immunofluorescence for subcellular localization\",\n      \"journal\": \"Pharmacogenetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with kinetics, protein normalization, localization; multiple orthogonal methods\",\n      \"pmids\": [\"15564882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"OATP1B1 together with MRP2 mediates transcellular transport of rifampin across LLC-PK1 cell monolayers co-expressing both transporters; directional transport was demonstrated for the first time for rifampin through this transporter pair.\",\n      \"method\": \"Porcine LLC-PK1 cells stably co-expressing OATP1B1 and MRP2; directional transport assays across monolayers\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro transcellular transport reconstitution, single lab, single study\",\n      \"pmids\": [\"15652233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Multiple naturally occurring flavonoids inhibit OATP1B1-mediated transport of DHEAS in a concentration-dependent manner in OATP1B1-expressing HeLa cells; biochanin A is among the most potent inhibitors (IC50 ~11 µM) and acts via a noncompetitive mechanism (Ki ~10 µM). Biochanin A is not itself a substrate of OATP1B1.\",\n      \"method\": \"OATP1B1-expressing HeLa cells; radiolabeled DHEAS uptake inhibition assays; kinetic analysis of inhibition mechanism\",\n      \"journal\": \"Drug metabolism and disposition\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro uptake assays with inhibition kinetics in OATP1B1-expressing vs. negative cells, multiple compounds\",\n      \"pmids\": [\"16081670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"OATP1B1 mediates hepatic uptake of enalapril with a Km of ~262 µM in HEK293 cells; double-transfected MDCK II cells expressing OATP1B1 and MRP2 showed significantly higher sinusoidal-to-canalicular vectorial flux of enalapril, demonstrating the coupled role of these two transporters in hepatic enalapril disposition.\",\n      \"method\": \"HEK293 cells transfected with OATP1B1 or OATP1B3; radiolabeled enalapril uptake kinetics; double-transfected MDCK II cells with OATP1B1 and MRP2; Transwell directional flux assays\",\n      \"journal\": \"The Journal of pharmacology and experimental therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with kinetics plus transcellular transport in polarized double-transfectant system\",\n      \"pmids\": [\"16627748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"OATP1B1 transcription is under dual nuclear receptor control: LXRα and FXR directly regulate OATP1B1 gene expression. Two functional FXR response elements and one LXRα response element were identified in the OATP1B1 promoter; direct receptor-promoter binding was confirmed by chromatin immunoprecipitation. LXRα or FXR agonists induced OATP1B1 mRNA in primary human hepatocytes, whereas PXR and CAR agonists did not.\",\n      \"method\": \"Promoter deletion/reporter gene assays; chromatin immunoprecipitation (ChIP); siRNA knockdown; primary human hepatocyte treatment with nuclear receptor ligands\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (reporter assays, ChIP, primary hepatocytes, siRNA) in a single comprehensive study\",\n      \"pmids\": [\"20827719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Maraviroc is a substrate of OATP1B1 with a Km of 33.9 µM, as demonstrated in a Xenopus laevis oocyte expression system. The SLCO1B1 521T>C polymorphism was associated with higher maraviroc trough plasma concentrations in HIV-infected patients.\",\n      \"method\": \"Xenopus laevis oocyte heterologous expression system; LC-MS/MS quantification; clinical pharmacokinetic analysis\",\n      \"journal\": \"Pharmacogenetics and genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro transport reconstitution in oocytes with kinetic parameters, supported by clinical PK data\",\n      \"pmids\": [\"21217360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Flavopiridol and its glucuronide metabolite are substrates of OATP1B1, as demonstrated in transiently transfected HEK-293 and MDCK-II cells. SLCO1B1 polymorphisms were associated with flavopiridol pharmacokinetics in a population pharmacokinetic model.\",\n      \"method\": \"Transient transfection of HEK-293 and MDCK-II cells with SLCO1B1; uptake assays; population pharmacokinetic modeling from clinical data\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro transport reconstitution validated by clinical PK data, two cell line systems\",\n      \"pmids\": [\"21072184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"OATP1B1 transports sorafenib-glucuronide (10.6-fold over control) in HEK293 cells stably transfected with OATP1B1; plasma levels of sorafenib-glucuronide were increased >8-fold in Oatp1b2-knockout mice. Introduction of human OATP1B1 in knockout mice partially restored clearance of sorafenib-glucuronide.\",\n      \"method\": \"Stably transfected HEK293 cells with OATP1B1; radiolabeled/LC-MS uptake assays; Oatp1b2-knockout and humanized OATP1B1-transgenic mice pharmacokinetic studies\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution combined with in vivo knockout and humanized transgenic mouse models\",\n      \"pmids\": [\"23340295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In vivo studies using oatp1a/1b-knockout and liver-specific OATP1B1-humanized mice established that OATP1B1 mediates hepatic uptake and clearance of statins (pravastatin, atorvastatin, simvastatin); oatp1a/1b-knockout mice showed up to 115-fold increased oral drug exposure and up to 196-fold lower hepatic drug distribution, partially restored by OATP1B1 knockin.\",\n      \"method\": \"Oatp1a/1b-knockout and liver-specific OATP1B1-humanized transgenic mice; pharmacokinetic studies with IV and oral administration; quantitative proteomics\",\n      \"journal\": \"Drug metabolism and disposition\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout and humanized transgenic mouse models with multiple statins, replicated across genotypes\",\n      \"pmids\": [\"24194513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"OATP1B1 mediates hepatic uptake of docetaxel in vivo; liver-specific expression of OATP1B1 in Oatp1a/1b-knockout mice nearly completely rescued the increased plasma levels of docetaxel seen in knockout mice after IV administration.\",\n      \"method\": \"Oatp1a/1b-knockout mice and liver-specific OATP1B1-humanized transgenic mice; in vivo pharmacokinetic studies with docetaxel; liver-to-plasma ratio measurements\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo functional rescue experiment in humanized transgenic mice, multiple human OATP isoforms tested\",\n      \"pmids\": [\"24825069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"OATP1B1 mediates uptake of nilotinib (Km 10.14 µM) and vandetanib (Km 2.72 µM) in CHO cells transfected with OATP1B1; canertinib, erlotinib, and pazopanib did not show substrate specificity toward OATP1B1.\",\n      \"method\": \"CHO cells transfected with OATP1B1; concentration-dependent cellular accumulation assays; Michaelis-Menten kinetic analysis\",\n      \"journal\": \"Drug metabolism and drug interactions\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro kinetic characterization, single lab, single method\",\n      \"pmids\": [\"24643910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"OATP1B1 function is regulated by tyrosine kinase-mediated phosphorylation at tyrosine residue 645. Inhibition of OATP1B1 by tyrosine kinase inhibitors (TKIs) such as nilotinib is predominantly noncompetitive and is associated with reduced phosphorylation at Y645. The Src kinase LYN was identified as a regulator of OATP1B1 activity using a siRNA kinome screen (779 kinases).\",\n      \"method\": \"Overexpressing HEK293 cells and primary hepatocytes; TKI transport inhibition assays; LC/MS-MS phosphoproteomics; siRNA kinome screen; in vivo rosuvastatin PK with nilotinib in mice\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — phosphoproteomics identification of modification site, siRNA functional screen, mutagenesis validation, in vivo confirmation; multiple orthogonal methods\",\n      \"pmids\": [\"33664059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"OATP1B1 function is affected by SLCO1B1 variants altering protein folding and degradation; deep mutational scanning of 137 SLCO1B1 missense variants identified 6 variants with <25% and 12 with ~50% of wild-type protein expression, with functional validation by transporter assays.\",\n      \"method\": \"Deep mutational scanning (DMS) using landing pad cell-based system with GFP fusion and FACS; next-generation sequencing; functional transport validation assays\",\n      \"journal\": \"Drug metabolism and disposition\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — high-throughput screening with functional validation, single lab, novel approach with some caveats for membrane proteins noted by authors\",\n      \"pmids\": [\"33658230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Preincubation with rifampicin and dasatinib potentiates inhibitory effects on OATP1B1-mediated transport by reducing Ki values (rifampicin 3-fold, dasatinib 2.1-fold for OATP1B1), without affecting plasma membrane localization of GFP-tagged OATP1B1 in HEK293 cells, as confirmed by time-lapse confocal microscopy.\",\n      \"method\": \"HEK293 stable cell lines with GFP-OATP1B1; transport inhibition assays with preincubation; Ki determination; confocal microscopy; human sandwich-cultured hepatocytes\",\n      \"journal\": \"Journal of pharmaceutical sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assays with mechanistic Ki, localization confirmed by confocal microscopy, multiple cell systems\",\n      \"pmids\": [\"28373111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Coexpression of OATP1B3 with OATP1B1 in HEK293 cells increases OATP1B3 plasma membrane expression while decreasing its apparent turnover rate, suggesting hetero-oligomerization modulates OATP1B3 function; this implies that single-transporter overexpression systems may over- or underestimate OATP1B1-related function.\",\n      \"method\": \"Co-immunoprecipitation; proximity ligation assay in HEK293 cells and human liver sections; membrane expression quantification; cholecystokinin-8 uptake assays\",\n      \"journal\": \"Drug metabolism and disposition\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal protein interaction demonstrated by Co-IP and PLA, functional consequences measured, confirmed in human liver tissue\",\n      \"pmids\": [\"32482756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Berberine promotes OATP1B1 expression and rosuvastatin uptake in HepG2 cells by inducing nuclear translocation and activation of FXR and LXRα; siRNA silencing of FXR or LXRα attenuated berberine-induced OATP1B1 expression.\",\n      \"method\": \"HepG2 cell treatment with berberine; rosuvastatin uptake assay; dual-luciferase reporter assay; siRNA knockdown of FXR and LXRα; Western blot of cytoplasm/nuclear fractions\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, siRNA, subcellular fractionation, functional transport), single lab\",\n      \"pmids\": [\"32292349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Functional analysis of rare SLCO1B1 variants in HEK293 cells showed that R57Q impairs both DCF and rosuvastatin transport without reducing protein expression, while R253Q reduces DCF uptake and increases rosuvastatin Km. N130D and N151S do not alter activity but increase protein expression. QTAP proteomics confirmed OATP1B1 protein abundance differences among variants.\",\n      \"method\": \"HEK293 cells overexpressing SLCO1B1 variants; uptake assays with DCF and rosuvastatin; LC-MS/MS-based QTAP proteomics; pharmacokinetic simulations\",\n      \"journal\": \"European journal of pharmaceutical sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro transport reconstitution with multiple substrates and protein quantification by proteomics, single lab\",\n      \"pmids\": [\"35752377\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"OATP1B1 (SLCO1B1) is a sodium-independent uptake transporter expressed exclusively at the basolateral (sinusoidal) membrane of human hepatocytes, where its liver-specific expression is driven by HNF1α (and modulated by FXR and LXRα); it mediates high-affinity hepatic uptake of bile acids, bilirubin conjugates, statins, rifampin, and numerous drugs, and works in concert with canalicular efflux transporters (especially MRP2) to achieve vectorial hepatobiliary transport; its activity is regulated post-translationally by LYN-mediated phosphorylation at tyrosine 645, and common loss-of-function variants (notably *5/V174A and *15/N130D+V174A) reduce transport capacity by impairing protein folding or intrinsic activity, leading to increased systemic drug exposure and statin-induced myopathy risk.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLCO1B1 encodes OATP1B1, a sodium-independent organic anion uptake transporter localized to the basolateral (sinusoidal) membrane of human hepatocytes that mediates hepatic clearance of bile acid conjugates, drugs, and their metabolites [#9, #3]. It transports a broad range of organic anions and pharmaceuticals, including sulfobromophthalein, bilirubin conjugates, statins (pravastatin), rifampin, enalapril, maraviroc, docetaxel, and glucuronide metabolites of sorafenib and gemfibrozil [#0, #2, #5, #14], with in vivo knockout and liver-specific humanized mouse models confirming its dominant role in hepatic uptake and systemic clearance of statins and chemotherapeutics [#19, #20, #18]. OATP1B1 achieves vectorial hepatobiliary transport by working in series with the canalicular efflux pump MRP2, as reconstituted in double-transfected polarized monolayers for estradiol glucuronide, pravastatin, rifampin, and enalapril [#2, #12, #14]. Its liver-restricted expression is driven by HNF1\\u03b1 binding to the minimal promoter [#1] and is further controlled by direct transcriptional regulation through FXR and LXR\\u03b1 response elements [#15, #26], while post-translationally its activity depends on LYN/Src-family tyrosine kinase phosphorylation at Tyr645, the site through which tyrosine kinase inhibitors noncompetitively suppress transport [#22]. Common and rare missense variants modulate function through distinct mechanisms: L193R causes intracellular retention and abolishes maturation, the *15 haplotype (N130D+V174A) reduces normalized Vmax to under 30% of wild-type while remaining surface-localized, and folding/expression effects across the variant landscape reduce protein abundance \\u2014 changes that lower hepatic clearance and increase systemic drug exposure in vivo [#3, #11, #23, #6].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established OATP1B1 as a high-affinity hepatic uptake transporter for endogenous organic anions, defining its substrate class biochemically.\",\n      \"evidence\": \"Radiolabeled uptake kinetics for bilirubin conjugates and sulfobromophthalein in stably transfected HEK293 cells\",\n      \"pmids\": [\"11134001\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Bilirubin transport role was later challenged\", \"Did not address membrane polarity or in vivo relevance\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Resolved where the transporter acts and why it is liver-specific, anchoring OATP1B1 to the sinusoidal membrane and identifying HNF1\\u03b1 as the driver of its tissue-restricted expression.\",\n      \"evidence\": \"Immunolocalization in human liver plus DNase footprinting, EMSA, and reporter assays in hepatic cell lines\",\n      \"pmids\": [\"11483603\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address additional transcriptional regulators identified later\", \"No post-translational regulation examined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrated that OATP1B1 functions as the uptake arm of a coupled vectorial transport system, working with MRP2 to move organic anions basal-to-apical across hepatocytes.\",\n      \"evidence\": \"Directional flux assays in OATP1B1/MRP2 double-transfected MDCK II monolayers\",\n      \"pmids\": [\"11748225\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconstituted in heterologous epithelium, not native hepatocytes\", \"Stoichiometry of coupling not defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Distinguished folding/trafficking defects from intrinsic activity defects among variants, showing L193R is retained intracellularly while *15 (N130D+V174A) is surface-localized but functionally impaired.\",\n      \"evidence\": \"Site-directed mutagenesis, immunofluorescence localization, and uptake kinetics with protein normalization in MDCK II and HEK293 cells\",\n      \"pmids\": [\"12196548\", \"12130747\", \"15564882\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which V174A lowers turnover not resolved at structural level\", \"Single-variant heterologous systems\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Extended the substrate range to clinically important drugs and linked variant transport defects to altered drug disposition in humans, establishing pharmacogenetic relevance.\",\n      \"evidence\": \"Rifampin uptake and PXR transactivation assays in HeLa cells; pravastatin pharmacokinetic study in genotyped volunteers\",\n      \"pmids\": [\"12490595\", \"12811365\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Clinical PK study was modest in size, single lab\", \"In vivo causality not isolated from other clearance routes\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Challenged the bilirubin-transporter assignment, with replicated negative uptake data questioning whether OATP1B1 is sufficient for bilirubin transport.\",\n      \"evidence\": \"Inducible stable transfection and bilirubin/BSP uptake assays in two cell lines\",\n      \"pmids\": [\"12670950\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Discrepancy with earlier positive bilirubin findings unresolved\", \"Possible differences in substrate presentation or cofactors not examined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined the mechanistic basis of a clinical drug-drug interaction, showing a glucuronide metabolite inhibits OATP1B1-mediated statin uptake.\",\n      \"evidence\": \"Cerivastatin uptake inhibition by gemfibrozil and its glucuronide in OATP2-expressing cells, with parallel CYP2C8 inhibition\",\n      \"pmids\": [\"15194707\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of transport vs metabolism inhibition in vivo not partitioned in this study\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Expanded transcriptional control beyond HNF1\\u03b1, identifying FXR and LXR\\u03b1 as direct nuclear-receptor regulators of OATP1B1 expression.\",\n      \"evidence\": \"Promoter reporter assays, ChIP, siRNA, and ligand treatment of primary human hepatocytes\",\n      \"pmids\": [\"20827719\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between HNF1\\u03b1 and nuclear-receptor inputs not integrated\", \"Physiological stimuli driving these receptors in vivo not defined here\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Provided in vivo proof that OATP1B1 governs hepatic uptake and systemic clearance of statins and drug glucuronides, moving beyond cell-based inference.\",\n      \"evidence\": \"Oatp1a/1b-knockout and liver-specific OATP1B1-humanized mice with statin and sorafenib-glucuronide pharmacokinetics\",\n      \"pmids\": [\"24194513\", \"23340295\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mouse humanization is partial; quantitative scaling to human uncertain\", \"Contribution of other OATP isoforms not fully separated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified post-translational kinase control of transporter activity, mapping LYN-mediated phosphorylation at Tyr645 as a regulatory node exploited by tyrosine kinase inhibitors.\",\n      \"evidence\": \"Phosphoproteomics, siRNA kinome screen, mutagenesis, and in vivo rosuvastatin PK with nilotinib\",\n      \"pmids\": [\"33664059\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals activating LYN toward OATP1B1 unknown\", \"How Y645 phosphorylation alters transport mechanistically not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed that OATP1B1 hetero-oligomerizes with OATP1B3, modulating membrane expression and turnover and complicating single-transporter functional estimates.\",\n      \"evidence\": \"Co-immunoprecipitation, proximity ligation assay in cells and human liver, and uptake assays\",\n      \"pmids\": [\"32482756\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional impact on OATP1B1 substrates specifically not quantified\", \"Stoichiometry and physiological extent of oligomerization unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Systematically separated folding/expression effects from intrinsic activity effects across rare variants, refining the genotype-to-function map.\",\n      \"evidence\": \"Deep mutational scanning and variant uptake assays with QTAP proteomics in HEK293 cells\",\n      \"pmids\": [\"33658230\", \"35752377\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"High-throughput membrane-protein assays carry expression-system caveats\", \"Clinical translation of many rare variants untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How transcriptional (HNF1\\u03b1/FXR/LXR\\u03b1), post-translational (LYN/Y645), and oligomerization inputs are integrated to set hepatic OATP1B1 transport capacity in vivo remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified regulatory model connecting transcription, phosphorylation, and oligomerization\", \"Structural basis of substrate recognition and transport cycle not established in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 2, 5, 14, 16, 18, 19]},\n      {\"term_id\": \"GO:0022857\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 9, 11, 24]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 2, 19]},\n      {\"term_id\": \"R-HSA-9748784\", \"supporting_discovery_ids\": [5, 19, 18]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MRP2\", \"ABCC2\", \"SLCO1B3\", \"LYN\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}