Gene Summary

Gene:SLCO1B1; solute carrier organic anion transporter family member 1B1
Summary:This gene encodes a liver-specific member of the organic anion transporter family. The encoded protein is a transmembrane receptor that mediates the sodium-independent uptake of numerous endogenous compounds including bilirubin, 17-beta-glucuronosyl estradiol and leukotriene C4. This protein is also involved in the removal of drug compounds such as statins, bromosulfophthalein and rifampin from the blood into the hepatocytes. Polymorphisms in the gene encoding this protein are associated with impaired transporter function. [provided by RefSeq, Mar 2009]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:solute carrier organic anion transporter family member 1B1
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: SLCO1B1 (cancer-related)

Jaerapong N, Jamil QA, Riha J, et al.
Organic anion‑transporting polypeptides contribute to the uptake of curcumin and its main metabolites by human breast cancer cells: Impact on antitumor activity.
Oncol Rep. 2019; 41(4):2558-2566 [PubMed] Related Publications
Curcumin is a natural polyphenolic compound with pronounced anticancer properties, despite its low bioavailability caused by extensive glucuronidation and sulfation. Information on the cellular uptake mechanisms and their contribution to the anticancer effects of curcumin and its biotransformation products is limited. The present study, therefore, investigated the role of organic anion‑transporting polypeptides (OATPs) in the cellular uptake of curcumin and its major metabolites in OATP‑expressing Chinese hamster ovary (CHO) and human ZR‑75‑1 breast cancer cells. The uptake rates for curcumin in OATP1B1‑, OATP1B3‑ and OATP2B1‑transfected CHO cells were 2‑ to 3‑fold higher than wild‑type cells. Curcumin sulfate was transported by all three OATPs, although to a much lesser extent, while uptake of tetrahydrocurcumin was the highest but only via OATP1B1 and OATP1B3. Notably, curcumin glucuronide did not exhibit any affinity for these OATPs. The increased mRNA levels of OATP1B1 in wild‑type human breast cancer ZR‑75‑1 cells compared with OATP1B1 knockdown cells was associated with a higher initial uptake of curcumin and tetrahydrocurcumin leading to decreased IC50 values. In conclusion, our data revealed that OATPs act as cellular uptake transporters for curcumin and its major metabolites, and this may also be applicable to patients undergoing cancer therapy.

Malinen MM, Ito K, Kang HE, et al.
Protein expression and function of organic anion transporters in short-term and long-term cultures of Huh7 human hepatoma cells.
Eur J Pharm Sci. 2019; 130:186-195 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
Human-derived hepatic cell lines are a valuable alternative to primary hepatocytes for drug metabolism, transport and toxicity studies. However, their relevance for investigations of drug-drug and drug-organic anion (e.g., bile acid, steroid hormone) interactions at the transporter level remains to be established. The aim of the present study was to determine the suitability of the Huh7 cell line for transporter-dependent experiments. Huh7 cells were cultured for 1 to 4 weeks and subsequently were analyzed for protein expression, localization and activity of solute carrier (SLC) and ATP-binding cassette (ABC) transporters involved in organic anion transport using liquid chromatography-tandem mass spectroscopy, immunocytochemistry, and model substrates [

Treenert A, Areepium N, Tanasanvimon S
Effects of ABCC2 and SLCO1B1 Polymorphisms on Treatment Responses in Thai Metastatic Colorectal Cancer Patients Treated with Irinotecan-Based Chemotherapy
Asian Pac J Cancer Prev. 2018; 19(10):2757-2764 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
Purpose: Irinotecan is an anticancer medicine which is used mostly in metastatic colorectal cancer (mCRC) treatment as second or third line chemotherapy. Several factors affect its efficacy and toxicity, including pharmacogenomics. This study aimed to investigate the impacts of ABCC2 and SLCO1B1 polymorphisms on treatment responses in irinotecan-based chemotherapy in 49 Thai mCRC patients. Materials and Methods: Forty-nine participants with mCRC enrolled in this study received irinotecan-based chemotherapy from January to June 2017. Genotypic analyses of ABCC2 (C>T, rs717620) and SLCO1B1 (A>G, rs2306283) were performed. Treatment responses were evaluated after at least three cycles of chemotherapy were given. Results: Allele frequencies of ABCC2 (C>T) and SLCO1B1 (A>G) were found at 18.37% and 78.57%, respectively. Neither was associated with treatment responses. However, combined genotypes of ABCC2 and SLCO1B1 tended to be associated with clinical benefits in terms of partial responses (PR) and stable disease (SD). All patients (100%) with at least one variant allele of SLCO1B1 and ABCC2 were in a PR or SD group, while patients with other genotypes had progressive disease (PD) at 45.5% to 70%, (p = 0.059). Conclusion: The combined effect of ABCC2 and SLCO1B1 polymorphisms tended to be associated with treatment responses in irinotecan-based treated mCRC patients. Therefore, such polymorphisms could be factors impacting inter-individual variation of irinotecan efficacy in Thai mCRC patients.

Lu H, Qin J, Han N, et al.
Banxia Xiexin Decoction Is Effective to Prevent and Control Irinotecan-Induced Delayed Diarrhea in Recurrent Small Cell Lung Cancer.
Integr Cancer Ther. 2018; 17(4):1109-1114 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
BACKGROUND: Irinotecan (CPT-11) can be used as a first-line therapeutic drug against extensive-stage small cell lung cancer (SCLC); it can also be used in second-line treatment for SCLC. CPT-11-induced delayed diarrhea restricts its clinical application. This study aimed to confirm whether Banxia Xiexin decoction was effective in preventing and controlling CPT-11-induced delayed diarrhea.
METHODS: A total of 27 patients with recurrent SCLC undergoing chemotherapy regimens including CPT-11 were enrolled for the study. UGT1A1*28, UGTlAl*6, ABCB1*2, and SLCO1B1*15 gene polymorphisms were detected. If delayed diarrhea occurred in the first cycle of chemotherapy, Banxia Xiexin decoction was orally administered for 5 consecutive days starting 1 day before the second cycle of chemotherapy to prevent and control the delayed diarrhea. The objective response, overall survival, and toxicity were recorded.
RESULTS: Complete response, partial response, and stable disease were observed in none, 6, and 10 patients, respectively. Delayed diarrhea occurred in 6 patients, and 4 of 5 patients were relieved or controlled using Banxia Xiexin decoction. The median overall survival was 6 months.
CONCLUSION: Banxia Xiexin decoction appeared to prevent and control delayed diarrhea induced by CPT-11 in this small observational study, and further study with a larger sample size, including potentially randomized trials, is suggested.

Weidle UH, Rohwedder I, Birzele F, et al.
LST1: A multifunctional gene encoded in the MHC class III region.
Immunobiology. 2018; 223(11):699-708 [PubMed] Related Publications
The LST1 gene is located in the MHC class III cluster between the MHC class I and II regions. While most genes in this cluster have been sufficiently characterised, a definitive function and expression pattern for LST1 still remains elusive. In the present review we describe its promotor, gene organisation, splice variants and expression in human tissues, cell lines and cancer. We focus on LST1 expression in inflammation and discuss known correlations with autoimmune diseases and cancer. Current data on LST1 polymorphisms and their known associations with pathologies are also discussed in detail. We summarize the potential functions that have been described for the full-length LST1 protein including its function as a transmembrane adaptor protein with inhibitory signal transduction and its role as a membrane scaffold facilitating the formation of tunnelling nanotubes. We also discuss further potential functions by compiling all known LST1-interacting proteins. Furthermore, we address knowledge gaps and conflictive issues regarding disease association, non-hematopoietic expression and the discrepancy between RNA and protein expression data.

Sato Y, Ueno H, Ioka T, et al.
SLCO1B1 Polymorphism Is a Drug Response Predictive Marker for Advanced Pancreatic Cancer Patients Treated With Gemcitabine, S-1, or Gemcitabine Plus S-1.
Pancreas. 2018 May/Jun; 47(5):637-642 [PubMed] Related Publications
OBJECTIVES: The aim of this study was to evaluate the effects of single-nucleotide polymorphisms (SNPs) on advanced pancreatic cancer risk and overall survival (OS) in a candidate-gene approach.
METHODS: Overall, 5438 SNPs in 219 candidate genes encoding several drug-metabolizing enzymes or transporters were analyzed. In the screening study, 3 SNPs were found associated with OS (P ≤ 0.0005). We validated these SNPs as part of the randomized phase 3 study (GEST study). The associations between OS and SNPs were investigated using log-rank test and Cox proportional hazards model.
RESULTS: From the GEST study, the SNP rs4149086 in the 3' UTR of the solute carrier organic anion transporter family member 1B1 (SLCO1B1) gene showed significant interaction with treatment (P = 0.02). In the gemcitabine group, the SNP was associated with short OS (hazard ratio [HR], 3.75; 95% confidence interval [CI], 1.30-10.8; P = 0.008) even after multiple-comparisons adjustment. In contrast, the SNP was not associated with OS in S-1 (HR, 0.77; 95% CI, 0.33-1.81; P = 0.55) or gemcitabine plus S-1 groups (HR, 1.18; 95% CI, 0.46-3.00; P = 0.72).
CONCLUSIONS: Patients with advanced pancreatic cancer with the rs4149086 AG or GG genotype may obtain good clinical results when treated with S-1-containing regimens.

Eldem İ, Yavuz D, Cumaoğullari Ö, et al.
SLCO1B1 Polymorphisms are Associated With Drug Intolerance in Childhood Leukemia Maintenance Therapy.
J Pediatr Hematol Oncol. 2018; 40(5):e289-e294 [PubMed] Related Publications
BACKGROUND: Therapy discontinuations and toxicities occur because of significant interindividual variations in 6-mercaptopurine (6-MP) and methotrexate (MTX) response during maintenance therapy of childhood acute lymphoblastic leukemia (ALL). 6-MP/MTX intolerance in some of the patients cannot be explained by thiopurine S-methyl transferase (TPMT) gene variants. In this study, we aimed to investigate candidate pharmacogenetic determinants of 6-MP and MTX intolerance in Turkish ALL children.
METHODS: In total, 48 children with ALL who had completed or were receiving maintenance therapy according to Children's Oncology Group (COG) protocols were enrolled. Fifteen single-nucleotide polymorphisms in 8 candidate genes that were related to drug toxicity or had a role in the 6-MP/MTX metabolism (TPMT, ITPA, MTHFR, IMPDH2, PACSIN2, SLCO1B1, ABCC4, and PYGL) were genotyped by competitive allele-specific PCR (KASP). Drug doses during maintenance therapy were modified according to the protocol.
RESULTS: The median drug dose intensity was 50% (28% to 92%) for 6-MP and 58% (27% to 99%) for MTX in the first year of maintenance therapy, which were lower than that scheduled in all patients. Among the analyzed polymorphisms, variant alleles in SLCO1B1 rs4149056 and rs11045879 were found to be associated with lower 6-MP/MTX tolerance.
CONCLUSIONS: SLCO1B1 rs4149056 and rs11045879 polymorphisms may be important genetic markers to individualize 6-MP/MTX doses.

Falkowski S, Woillard JB, Postil D, et al.
Common variants in glucuronidation enzymes and membrane transporters as potential risk factors for colorectal cancer: a case control study.
BMC Cancer. 2017; 17(1):901 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
BACKGROUND: Associations between polymorphisms of UDP-glucuronosyltransferases (UGTs) or efflux transporters (e.g., P-glycoprotein and MRP2) and different types of cancer have been described, whereas the role of influx transporters (e.g. OATP1B1 and OATP2B1) has been seldom explored. The GenColon study investigated potential associations between variant alleles of UGTs, efflux and influx transporters and CRC.
METHODS: Three hundred CRC cases were matched with 300 controls for age, sex and enrolment site. Fifteen SNPs in UGT1A6-9, UGT2B7, ABCB1, ABCC2, SLCO1B1 and SLCO2B1 genes were characterized using Taqman® PCR. Using multivariate conditional logistic regression, we investigated the relationships between CRC and "environmental" risk factors (physical activity, housing and working areas, consumption of red meat, tobacco, alcohol); genetic polymorphisms, in the study population and in the subgroups with "environmental" risk factors.
RESULTS: No significant association was observed for the analyzed SNPs (or haplotypes). However, an increased CRC risk was found in carriers of the UGT1A8 rs1042597-G variant allele (additive risk OR = 3.39[1.29-8.89], p = 0.02951) in the subgroup of meat-consumers (n = 84), and in carriers of the ABCB1 rs1045642-T (exon26) variant allele (additive risk; OR = 1.89[1.10-3.39], p = 0.0257) in the "never alcohol consumption subgroup" (n = 125). In addition, as previously reported, the following CRC risk factors were identified: absence of physical activity (OR = 6.35[3.70-10.9], p < 0.0001), living or working in rural or mix area (OR = 2.50[1.48-4.23], p = 0.0006 and OR = 2.99[1.63-5.48], p = 0.004, respectively) and tobacco exposure >30 years (3.37[1.63-6.96], p = 0.0010).
CONCLUSIONS: Variant genotypes of influx transporters (OATP1B1 and 2B1) were not associated with CRC. This study confirmed the influence of lifestyle factors, but not the previously reported detrimental effect of SNPs in intestinal UGTs or efflux transporters, except for a UGT1A8 variant in subjects consuming meat and the exon 26 SNP of ABCB1 in the never alcohol consumption subgroup.
TRIAL REGISTRATION: Registered in Direction Générale de la Santé the 1st July 2008 under the number DGS2008-0144.

D'Aloia A, Berruti G, Costa B, et al.
RalGPS2 is involved in tunneling nanotubes formation in 5637 bladder cancer cells.
Exp Cell Res. 2018; 362(2):349-361 [PubMed] Related Publications
RalGPS2 is a Ras-independent Guanine Nucleotide Exchange Factor (GEF) for RalA containing a PH domain and an SH3-binding region and it is involved in several cellular processes, such as cytokinesis, control of cell cycle progression, differentiation, cytoskeleton organization and rearrangement. Up to now, few data have been published regarding RalGPS2 role in cancer cells, and its involvement in bladder cancer is yet to be established. In this paper we demonstrated that RalGPS2 is expressed in urothelial carcinoma-derived 5637 cancer cells and is essential for cellular growth. These cells produces thin membrane protrusions that displayed the characteristics of actin rich tunneling nanotubes (TNTs) and here we show that RalGPS2 is involved in the formation of these cellular protrusions. In fact the overexpression of RalGPS2 or of its PH-domain increased markedly the number and the length of nanotubes, while the knock-down of RalGPS2 caused a strong reduction of these structures. Moreover, using a series of RalA mutants impaired in the interaction with different downstream components (Sec5, Exo84, RalBP1) we demonstrated that the interaction of RalA with Sec5 is required for TNTs formation. Furthermore, we found that RalGPS2 interacts with the transmembrane MHC class III protein leukocyte specific transcript 1 (LST1) and RalA, leading to the formation of a complex which promotes TNTs generation. These findings allow us to add novel elements to molecular models that have been previously proposed regarding TNTs formation.

Wu MR, Liu HM, Lu CW, et al.
Organic anion-transporting polypeptide 1B3 as a dual reporter gene for fluorescence and magnetic resonance imaging.
FASEB J. 2018; 32(3):1705-1715 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
Reporter proteins have broad applications in visualizing molecular events at the cellular, tissue and whole-body levels. Transmembrane transporters recognizing specific molecular domains are of particular interest because they enable the migration of signal-source molecules from the extracellular space to the cytoplasm for subsequent application in multimodality imaging. Organic anion-transporting polypeptides (OATPs) have demonstrated their MRI reporter efficacy. We further expanded their use as a dual-modality reporter in MRI and noninvasive in vivo imaging system (IVIS). We overexpressed OATP1B3 in the HT-1080 sarcoma cell line. Both Gd-EOB-DTPA, an MRI contrast agent, and indocyanine green (ICG), a near-infrared fluorescent dye that provides better deep-tissue detection because of its long wavelength, could be delivered to the intracellular space and imaged in a tumor-bearing nude mouse model. Our in vivo dual-imaging reporter system achieved high sensitivity in MRI and observation periods lasting as long as 96 h in IVIS. Because of the superior temporal and spatial resolutions and the clinical availability of both ICG and Gd-EOB-DTPA, this dual-imaging OATP1B3 system will find biomedical use in tumor biology, stem cell trafficking, and tissue engineering.-Wu, M.-R., Liu, H.-M., Lu, C.-W., Shen, W.-H., Lin, I.-J., Liao, L.-W., Huang, Y.-Y., Shieh, M.-J., Hsiao, J.-K. Organic anion-transporting polypeptide 1B3 as a dual reporter gene for fluorescence and magnetic resonance imaging.

Yang L, Wu H, Gelder TV, et al.
SLCO1B1 rs4149056 genetic polymorphism predicting methotrexate toxicity in Chinese patients with non-Hodgkin lymphoma.
Pharmacogenomics. 2017; 18(17):1557-1562 [PubMed] Related Publications
AIM: To investigate the impact of polymorphisms in the FPGS, GGH and SLCO1B1 genes on high dose methotrexate (HD-MTX) related toxicity in Chinese patients with non-Hodgkin lymphoma (NHL).
MATERIALS & METHODS: We analyzed FPGS (rs10106), GGH (rs719235, rs10464903, rs12681874), SLCO1B1 (rs4149056) genetic polymorphisms in 105 Chinese patients with NHL treated with HD-MTX.
RESULTS: There was a statistically significant impact of the SLCO1B1 rs4149056 polymorphism on hepatotoxicity. Patients with TC and CC genotype had more hepatotoxicity than TT genotype (60 vs 32.94%, p = 0.025). After adjusting for disease stage, dosage, infusion time and therapy method, SLCO1B1 rs4149056 genotype remained significantly associated with hepatotoxicity (p = 0.028).
CONCLUSION: SLCO1B1 rs4149056 genetic variants can affect the HD-MTX-related toxicity in Chinese patients with NHL.

Megias-Vericat JE, Martinez-Cuadron D, Herrero MJ, et al.
Pharmacogenetics of Metabolic Genes of Anthracyclines in Acute Myeloid Leukemia.
Curr Drug Metab. 2018; 19(1):55-74 [PubMed] Related Publications
BACKGROUND: Anthracyclines in combination with cytarabine have been the standard therapy for acute myeloid leukemia (AML) for decades with high efficacy. However, the majority of patients will show initial resistance or will relapse after initial complete remission. Genetic variability in genes involved in anthracyclines metabolic pathway could be one of the causes of the interindividual differences in clinical outcomes.
METHODS: A systematic review of published studies in AML cohorts was carried out in order to analyze the influence of polymorphisms in genes of anthracycline metabolism on efficacy and toxicity.
RESULTS: Polymorphisms in the main enzymes of anthracyclines metabolism (CBR, AKR, NQO1, NOS3) have been related to lower enzymatic activity and higher cardiotoxicity. Moreover, variant alleles in the genes of carcinogens and chemotherapy neutralizing enzymes (GST, SULT, NADP(H) oxidase) have been associated with ROS generation and drug efficacy, influencing the survival rates and cardiac toxicities. In addition, genetic variability in the transporters of anthracyclines could affect the intake in cells, including influx (SLC28A3, SLC22A12, SLCO1B1) and efflux transporters (ABCB1, ABCC1, ABCC3, ABCG2).
CONCLUSION: The knowledge of the role of pharmacogenetics in anthracyclines metabolism could explain the differences observed in their disposition in leukemic cells. These genetic variants are proposed biomarkers in clinical practice in order to individualize chemotherapy schemes, potentially increasing the effectiveness and reducing the toxicities.

Giletti A, Vital M, Lorenzo M, et al.
Methotrexate pharmacogenetics in Uruguayan adults with hematological malignant diseases.
Eur J Pharm Sci. 2017; 109:480-485 [PubMed] Related Publications
BACKGROUND: Individual variability is among the causes of toxicity and interruption of treatment in acute lymphoblastic leukemia (ALL) and severe non-Hodgkin lymphoma (NHL) patients under protocols including Methotrexate (MTX): 2,4-diamino-N10-methyl propyl-glutamic acid.
METHODS: 41 Uruguayan patients were recruited. Gene polymorphisms involved in MTX pathway were analyzed and their association with treatment toxicities and outcome was evaluated.
RESULTS: Genotype distribution and allele frequency were determined for SLC19A1 G
CONCLUSIONS: The associations found between gene polymorphisms and toxicities in this small cohort are encouraging for a more extensive research to gain a better dose individualization in adult ALL and NHL patients. Besides, genotype distribution showed to be different from other populations, reinforcing the idea that genotype data from other populations should not be extrapolated to ours.

Liu SG, Gao C, Zhang RD, et al.
Polymorphisms in methotrexate transporters and their relationship to plasma methotrexate levels, toxicity of high-dose methotrexate, and outcome of pediatric acute lymphoblastic leukemia.
Oncotarget. 2017; 8(23):37761-37772 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
High-dose methotrexate (HDMTX) plays an important role in the treatment of acute lymphoblastic leukemia (ALL) although there is great inter-patient variability in the efficacy and toxicity of MTX. The relationship between polymorphisms in genes encoding MTX transporters and MTX response is controversial. In the present study, 322 Chinese children with standard- and intermediate-risk ALL were genotyped for 12 polymorphisms. SLCO1B1 rs10841753 showed a significant association with plasma MTX levels at 48 h (P = 0.017). Patients who had the ABCB1 rs1128503 C allele had longer duration of hospitalization than did those with the TT genotype (P = 0.006). No association was found between oral mucositis and any polymorphism. Long-term outcome was worse in patients with the SLCO1B1 rs4149056 CC genotype than in patients with TT or TC (5-year event-free survival [EFS] 33.3 ± 19.2% vs. 90.5 ± 1.7%, P < 0.001), and was worse in patients with the SCL19A1 rs2838958 AA genotype than in patients with AG or GG (5-year EFS 78.5 ± 4.6% vs. 92.2 ± 1.8%, P = 0.008). Multiple Cox regression analyses revealed associations of minimal residual disease (MRD) at day 33 (hazard ratio 3.458; P = 0.002), MRD at day 78 (hazard ratio 6.330; P = 0.001), SLCO1B1 rs4149056 (hazard ratio 12.242; P < 0.001), and SCL19A1 rs2838958 (hazard ratio 2.324; P = 0.019) with EFS. Our findings show that polymorphisms in genes encoding MTX transporters substantially influence the kinetics and response to HDMTX therapy in childhood ALL.

Dudenkov TM, Ingle JN, Buzdar AU, et al.
SLCO1B1 polymorphisms and plasma estrone conjugates in postmenopausal women with ER+ breast cancer: genome-wide association studies of the estrone pathway.
Breast Cancer Res Treat. 2017; 164(1):189-199 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
BACKGROUND: Estrone (E1), the major circulating estrogen in postmenopausal women, promotes estrogen-receptor positive (ER+) breast tumor growth and proliferation. Two major reactions contribute to E1 plasma concentrations, aromatase (CYP19A1) catalyzed E1 synthesis from androstenedione and steroid sulfatase (STS) catalyzed hydrolysis of estrone conjugates (E1Cs). E1Cs have been associated with breast cancer risk and may contribute to tumor progression since STS is expressed in breast cancer where its activity exceeds that of aromatase.
METHODS: We performed genome-wide association studies (GWAS) to identify SNPs associated with variation in plasma concentrations of E1Cs, E1, and androstenedione in 774 postmenopausal women with resected early-stage ER+ breast cancer. Hormone concentrations were measured prior to aromatase inhibitor therapy.
RESULTS: Multiple SNPs in SLCO1B1, a gene encoding a hepatic influx transporter, displayed genome-wide significant associations with E1C plasma concentrations and with the E1C/E1 ratio. The top SNP for E1C concentrations, rs4149056 (p = 3.74E-11), was a missense variant that results in reduced transporter activity. Patients homozygous for the variant allele had significantly higher average E1C plasma concentrations than did other patients. Furthermore, three other SLCO1B1 SNPs, not in LD with rs4149056, were associated with both E1C concentrations and the E1C/E1 ratio and were cis-eQTLs for SLCO1B3. GWAS signals of suggestive significance were also observed for E1, androstenedione, and the E1/androstenedione ratio.
CONCLUSION: These results suggest a mechanism for genetic variation in E1C plasma concentrations as well as possible SNP biomarkers to identify ER+ breast cancer patients for whom STS inhibitors might be of clinical value.

Herraez E, Sanchez-Vicente L, Macias RIR, et al.
Usefulness of the MRP2 promoter to overcome the chemoresistance of gastrointestinal and liver tumors by enhancing the expression of the drug transporter OATP1B1.
Oncotarget. 2017; 8(21):34617-34629 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
Tumor response to chemotherapy is often limited by drug export through ABC proteins. To overcome this problem, here we have investigated the usefulness of inducing the expression of the multidrug uptake transporter OATP1B1 under the control of the MRP2 promoter (MRP2pr). Human hepatoma cells (Alexander) were transfected with MRP2pr fragments of different length fused to the firefly luciferase ORF in order to select the shortest fragment with the highest response to dexamethasone, which was subsequently used to generate the chimeric construct MRP2pr-OATP1B1-V5. Hepatoma cells transduced with MRP2pr-OATP1B1-V5 resulted in dexamethasone-sensitive inducible OATP1B1 expression and enhanced selective antitumor response to OATP1B1 substrates (paclitaxel, Bamet-R2 and Bamet-UD2). In human colon cancer cells LS174T/R, used as a model of endogenous chemoresistance due to MRP2 overexpression, MRP2pr-OATP1B1 induced OATP1B1 expression together with chemosensitivity to OATP1B1 substrates. In nude mice, xenografted tumors formed by LS174T/R cells transduced with MRP2pr-OATP1B1 plus treatment with dexamethasone were markedly sensitized to Bamet-UD2. In conclusion, the induced expression of anticancer drug uptake transporters, under the control of promoters of ABC proteins involved in chemoresistance, constitutes an interesting approach to overcome the poor response of cancer to chemotherapy due to reduced drug uptake and/or enhanced drug export.

Rudin S, Marable M, Huang RS
The Promise of Pharmacogenomics in Reducing Toxicity During Acute Lymphoblastic Leukemia Maintenance Treatment.
Genomics Proteomics Bioinformatics. 2017; 15(2):82-93 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
Pediatric acute lymphoblastic leukemia (ALL) affects a substantial number of children every year and requires a long and rigorous course of chemotherapy treatments in three stages, with the longest phase, the maintenance phase, lasting 2-3years. While the primary drugs used in the maintenance phase, 6-mercaptopurine (6-MP) and methotrexate (MTX), are necessary for decreasing risk of relapse, they also have potentially serious toxicities, including myelosuppression, which may be life-threatening, and gastrointestinal toxicity. For both drugs, pharmacogenomic factors have been identified that could explain a large amount of the variance in toxicity between patients, and may serve as effective predictors of toxicity during the maintenance phase of ALL treatment. 6-MP toxicity is associated with polymorphisms in the genes encoding thiopurine methyltransferase (TPMT), nudix hydrolase 15 (NUDT15), and potentially inosine triphosphatase (ITPA), which vary between ethnic groups. Moreover, MTX toxicity is associated with polymorphisms in genes encoding solute carrier organic anion transporter family member 1B1 (SLCO1B1) and dihydrofolate reductase (DHFR). Additional polymorphisms potentially associated with toxicities for MTX have also been identified, including those in the genes encoding solute carrier family 19 member 1 (SLC19A1) and thymidylate synthetase (TYMS), but their contributions have not yet been well quantified. It is clear that pharmacogenomics should be incorporated as a dosage-calibrating tool in pediatric ALL treatment in order to predict and minimize the occurrence of serious toxicities for these patients.

Green SM, Kaipainen A, Bullock K, et al.
Role of OATP transporters in steroid uptake by prostate cancer cells in vivo.
Prostate Cancer Prostatic Dis. 2017; 20(1):20-27 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
BACKGROUND: Epidemiologic and in vitro studies suggest that SLCO-encoded organic anion transporting polypeptide (OATP) transporters influence the response of prostate cancer (PCa) to androgen deprivation by altering intratumor androgens. We have previously shown that castration-resistant metastases express multiple SLCO transporters at significantly higher levels than primary PCa, suggesting that OATP-mediated steroid transport is biologically relevant in advanced disease. However, whether OATP-mediated steroid transport can actually modify prostate tumor androgen levels in vivo has never been demonstrated.
METHODS: We sought to determine whether OATP-mediated steroid transport can measurably alter PCa androgen levels in vivo. We evaluated the uptake of dehydroepiandrosterone (DHEAS), E1S and testosterone in LNCaP cells engineered to express OATP1B1, 1B3, 2B1 or 4A1. We measured the uptake via administration of tritiated steroids to castrate mice bearing vector control or OATP1B1-, 2B1- or 4A1-expressing xenografts. We treated tumor-bearing mice with DHEAS and testosterone at physiologically relevant levels and measured intratumor accumulation of administered steroids by mass spectrometry.
RESULTS: OATP1B1- and 2B-expressing xenografts each showed a threefold increase in tritiated-DHEAS uptake vs vector controls (P=0.002 and P=0.036, respectively). At circulating DHEAS levels similar to those in abiraterone-treated men (~15 μg dl
CONCLUSIONS: OATP transporters measurably alter DHEAS uptake and intratumor androgen levels in prostate tumors in vivo, even at circulating androgen levels achieved in abiraterone-treated patients. These novel data emphasize the continued need to inhibit ligand-mediated androgen receptor signaling in PCa tumors, and support prospective evaluation of studies designed to test inhibition of OATP-mediated DHEAS uptake and utilization.

Durmus S, van Hoppe S, Schinkel AH
The impact of Organic Anion-Transporting Polypeptides (OATPs) on disposition and toxicity of antitumor drugs: Insights from knockout and humanized mice.
Drug Resist Updat. 2016; 27:72-88 [PubMed] Related Publications
It is now widely accepted that organic anion-transporting polypeptides (OATPs), especially members of the OATP1A/1B family, can have a major impact on the disposition and elimination of a variety of endogenous molecules and drugs. Owing to their prominent expression in the sinusoidal plasma membrane of hepatocytes, OATP1B1 and OATP1B3 play key roles in the hepatic uptake and plasma clearance of a multitude of structurally diverse anti-cancer and other drugs. Here, we present a thorough assessment of the currently available OATP1A and OATP1B knockout and transgenic mouse models as key tools to study OATP functions in vivo. We discuss recent studies using these models demonstrating the importance of OATPs, primarily in the plasma and hepatic clearance of anticancer drugs such as taxanes, irinotecan/SN-38, methotrexate, doxorubicin, and platinum compounds. We further discuss recent work on OATP-mediated drug-drug interactions in these mouse models, as well as on the role of OATP1A/1B proteins in the phenomenon of hepatocyte hopping, an efficient and flexible way of liver detoxification for both endogenous and exogenous substrates. Interestingly, glucuronide conjugates of both the heme breakdown product bilirubin and the protein tyrosine kinase-targeted anticancer drug sorafenib are strongly affected by this process. The clinical relevance of variation in OATP1A/1B activity in patients has been previously revealed by the effects of polymorphic variants and drug-drug interactions on drug toxicity. The development of in vivo tools to study OATP1A/1B functions has greatly advanced our mechanistic understanding of their functional role in drug pharmacokinetics, and their implications for therapeutic efficacy and toxic side effects of anticancer and other drug treatments.

Drenberg CD, Paugh SW, Pounds SB, et al.
Inherited variation in OATP1B1 is associated with treatment outcome in acute myeloid leukemia.
Clin Pharmacol Ther. 2016; 99(6):651-60 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
Using broad interrogation of clinically relevant drug absorption, distribution, metabolism, and excretion (ADME) genes on the DMET platform, we identified a genetic variant in SLCO1B1 (rs2291075; c.597C>T), encoding the transporter OATP1B1, associated with event-free (P = 0.006, hazard ratio = 1.74) and overall survival (P = 0.012, hazard ratio = 1.85) in children with de novo acute myeloid leukemia (AML). Lack of SLCO1B1 expression in leukemic blasts suggested the association might be due to an inherited rather than a somatic effect. rs2291075 was in strong linkage with known functional variants rs2306283 (c.388A>G) and rs4149056 (c.521T>C). Functional studies in vitro determined that four AML-directed chemotherapeutics (cytarabine, daunorubicin, etoposide, and mitoxantrone) are substrates for OATP1B1 and the mouse ortholog Oatp1b2. In vivo pharmacokinetic studies using Oatp1b2-deficient mice further confirmed our results. Collectively, these findings demonstrate an important role for OATP1B1 in the systemic pharmacokinetics of multiple drugs used in the treatment of AML and suggest that inherited variability in host transporter function influences the effectiveness of therapy.

Chen S, Villeneuve L, Jonker D, et al.
ABCC5 and ABCG1 polymorphisms predict irinotecan-induced severe toxicity in metastatic colorectal cancer patients.
Pharmacogenet Genomics. 2015; 25(12):573-83 [PubMed] Related Publications
OBJECTIVE: Irinotecan is a cytotoxic agent used widely for the treatment of solid tumors, particularly for metastatic colorectal cancers. Treatment with this drug frequently results in severe neutropenia and diarrhea that can markedly impact the course of treatment and patients' quality of life. Pharmacogenomic tailoring of irinotecan-based chemotherapy has been the subject of several investigations, but with limited data on ATP-binding cassette (ABC) and solute carrier (SLC) transporter genes.
MATERIALS AND METHODS: In this study, we aimed to discover toxicity-associated markers in seven transporter genes participating in irinotecan pharmacokinetics involving the ABC transporter genes ABCB1, ABCC1, ABCC2, ABCC5, ABCG1, and ABCG2 and the solute carrier organic anion transporter gene SLCO1B1 and using a haplotype-tagging single-nucleotide polymorphisms (n=210 htSNPs) strategy. The profiles of 167 metastatic colorectal cancer Canadian patients treated with FOLFIRI-based regimens were examined and the findings were replicated in an independent cohort of 250 Italian patients.
RESULTS: In combined cohorts, a two-marker ABCC5 rs3749438 and rs10937158 haplotype (T-C) predicted lower risk of severe diarrhea [odds ratio (OR) of 0.43; P=0.001]. The co-occurrence of ABCG1 rs225440T and ABCC5 rs2292997A predicted the risk of severe neutropenia (OR=5.93; P=0.0002), which was further improved when incorporating the well-known risk marker UGT1A1*28 rs8175347 (OR=7.68; P<0.0001). In contrast, carriers of one protective marker (UGT1 rs11563250G) but none of these risk alleles experienced significantly less severe neutropenia (8.2 vs. 34.0%; P<0.0001).
CONCLUSION: This combination of predictive genetic markers could potentially lead to better risk assessment and may thus improve personalized treatment.

Chen Y, Shen Z
Gene polymorphisms in the folate metabolism and their association with MTX-related adverse events in the treatment of ALL.
Tumour Biol. 2015; 36(7):4913-21 [PubMed] Related Publications
The antifolate drug methotrexate (MTX) is widely used in the treatment of various neoplastic diseases, including acute lymphoblastic leukemia (ALL). MTX significantly increases cure rates and improves patients' prognosis. Despite that it achieved remarkable clinical success, a large number of patients still suffer from treatment toxicities or side effects. Even to this date, chemotherapeutic regiments have not been personalized because of interindividual differences that affect MTX response, especially polymorphisms in key genes. The pharmacological pathway of MTX in cells is useful to identify gene polymorphisms that influence the process of treatment. The aim of this review was to discuss the gene polymorphisms of drug-metabolizing enzymes in the MTX pathway and their toxicities on ALL treatment.

Suzuki R, Fukushima H, Noguchi E, et al.
Influence of SLCO1B1 polymorphism on maintenance therapy for childhood leukemia.
Pediatr Int. 2015; 57(4):572-7 [PubMed] Related Publications
BACKGROUND: Management of the adverse effects of chemotherapy is essential to improve outcome of children with leukemia. Some genetic polymorphisms can predict treatment-related toxicity, and be used individually in dose modification of 6-mercaptopurine (6-MP) and methotrexate (MTX) in maintenance therapy for childhood acute lymphoblastic leukemia (ALL). We investigated associations between clinical course and candidate gene polymorphisms less evaluated in Japanese patients.
METHODS: Fifty-three children who received maintenance chemotherapy were enrolled in this study. The scheduled dose of oral 6-MP was 40 mg/m(2) daily and that of oral MTX was 25 mg/m(2) weekly. The doses were adjusted according to white blood cell count (target range, 2.5-3.5 × 10(9) /L) and aspartate aminotransferase and alanine aminotransferase level (< 750 IU/L). Eight polymorphisms in six candidate genes, TPMT, ITPA, MRP4, MTHFR, RFC1, and SLCO1B1, were genotyped using the Taqman PCR method. Clinical course was reviewed retrospectively from medical records.
RESULTS: The average dose of 6-MP was lower in the patients with at least one variant allele at SLCO1B1 c.521 T > C than in the patients with wild homozygous genotype. The other analyzed polymorphisms were not associated with toxicity, 6-MP, or MTX dose.
CONCLUSIONS: Polymorphism of SLCO1B1 c.521 T > C could be a strong predictor of 6-MP dose reduction in maintenance chemotherapy in childhood ALL.

Crona DJ, Ramirez J, Qiao W, et al.
Clinical validity of new genetic biomarkers of irinotecan neutropenia: an independent replication study.
Pharmacogenomics J. 2016; 16(1):54-9 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
The overall goal of this study was to provide evidence for the clinical validity of nine genetic variants in five genes previously associated with irinotecan neutropenia and pharmacokinetics. Variants associated with absolute neutrophil count (ANC) nadir and/or irinotecan pharmacokinetics in a discovery cohort of cancer patients were genotyped in an independent replication cohort of 108 cancer patients. Patients received single-agent irinotecan every 3 weeks. For ANC nadir, we replicated UGT1A1*28, UGT1A1*93 and SLCO1B1*1b in univariate analyses. For irinotecan area under the concentration-time curve (AUC0-24), we replicated ABCC2 -24C>T; however, ABCC2 -24C>T only predicted a small fraction of the variance. For SN-38 AUC0-24 and the glucuronidation ratio, we replicated UGT1A1*28 and UGT1A1*93. In addition to UGT1A1*28, this study independently validated UGT1A1*93 and SLCO1B1*1b as new predictors of irinotecan neutropenia. Further demonstration of their clinical utility will optimize irinotecan therapy in cancer patients.

Pu Z, Zhang X, Chen Q, et al.
Establishment of an expression platform of OATP1B1 388GG and 521CC genetic polymorphism and the therapeutic effect of tamoxifen in MCF-7 cells.
Oncol Rep. 2015; 33(5):2420-8 [PubMed] Related Publications
The present study was designed to evaluate the gene polymorphisms of organic anion transporting polypeptide 1B1 (OATP1B1) in predicting the therapeutic efficacy of tamoxifen (TAM) for MCF-7. Established plasmids OATP1Bl wild-type 388GG and 521CC were transfected into MCF-7 cells and used to determine whether the gene polymorphisms affected the therapeutic efficacy of TAM for MCF-7. The established plasmids pcDNA3.1(-)-OATP1B1 wild-type 388GG and 521CC were digested by restriction enzymes and analyzed by gene sequencing. The gene polymorphisms of OATP1Bl in MCF-7 breast cancer cells were examined by RT-PCR and western blot analysis. The results showed that the mutations of OATP1B1 388GG and 521CC led to a decrease of the inhibition and apoptotic rates of MCF-7 cells, albeit not significantly compared to the OATP1B1 group. The G₀/G₁ phase length ratio was reduced, and the S and G₂M phases were increased in the OATP1B1 388GG and 521CC groups, although not significantly compared to the OATP1B1 group. The mutations of OATP1B1 388GG and 521CC inhibited the activity of OATP1B1 protein, restrained the turnover capacity of OATP1B1 and reduced the entrance of TAM into MCF-7 cells, resulting in weakened efficacy of TAM in the treatment of breast cancer.

Zhang X, Pu Z, Ge J, et al.
Association of CYP2D6*10, OATP1B1 A388G, and OATP1B1 T521C polymorphisms and overall survival of breast cancer patients after tamoxifen therapy.
Med Sci Monit. 2015; 21:563-9 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
BACKGROUND: The global incidence of breast cancer is increasing, mainly due to the sharp rise in breast cancer incidence in Asia. The aim of this study was to evaluate the association of CYP2D6*10 (c.100C>T and c.1039C>T), OATP1B1 A388G, and OATP1B1 T521C polymorphisms with overall survival (OS) for hormone receptor (estrogen receptor or progesterone receptor)-positive tumors (ER+/PR+) breast cancer patients after adjuvant tamoxifen (TAM) therapy.
MATERIAL AND METHODS: We included 296 invasive breast cancer patients with hormone receptor-positive tumors during the period 2002-2009. We collected patient data, including clinical features, TAM therapy, and survival status. Archived paraffin blocks from surgery were the source of tissue for genotyping. CYP2D6*10, OATP1B1 A388G, and T521C polymorphisms were detected by direct sequencing of genomic DNA. OS was assessed with Kaplan-Meier analysis, while the Cox proportional hazards model was used to implement multivariate tests for the prognostic significance.
RESULTS: There was a significant difference in OS between OATP1B1 T521C wild-type and the mutant genotype C carrier (P=0.034). However, there was no difference in overall survival between wild-type and carrier groups for CYP2D6*10 (P=0.096) and OATP1B1 A388G (P=0.388), respectively.
CONCLUSIONS: These results suggest that the OATP1B1 T521C mutation may be an independent prognostic marker for breast cancer patients using TAM therapy.

Lee E, Luo J, Su YC, et al.
Hormone metabolism pathway genes and mammographic density change after quitting estrogen and progestin combined hormone therapy in the California Teachers Study.
Breast Cancer Res. 2014; 16(6):477 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
INTRODUCTION: Mammographic density (MD) is a strong biomarker of breast cancer risk. MD increases after women start estrogen plus progestin therapy (EPT) and decreases after women quit EPT. A large interindividual variation in EPT-associated MD change has been observed, but few studies have investigated genetic predictors of the EPT-associated MD change. Here, we evaluate the association between polymorphisms in hormone metabolism pathway genes and MD changes when women quit EPT.
METHODS: We collected mammograms before and after women quit EPT and genotyped 405 tagging single nucleotide polymorphisms (SNPs) in 30 hormone metabolism pathway genes in 284 non-Hispanic white participants of the California Teachers Study (CTS). Participants were ages 49 to 71 years at time of mammography taken after quitting EPT. We assessed percent MD using a computer-assisted method. MD change was calculated by subtracting MD of an 'off-EPT' mammogram from MD of an 'on-EPT' (that is baseline) mammogram. Linear regression analysis was used to investigate the SNP-MD change association, adjusting for the baseline 'on-EPT' MD, age and BMI at time of baseline mammogram, and time interval and BMI change between the two mammograms. An overall pathway and gene-level summary was obtained using the adaptive rank truncated product (ARTP) test. We calculated 'P values adjusted for correlated tests (P(ACT))' to account for multiple testing within a gene.
RESULTS: The strongest associations were observed for rs7489119 in SLCO1B1, and rs5933863 in ARSC. SLCO1B1 and ARSC are involved in excretion and activation of estrogen metabolites of EPT, respectively. MD change after quitting was 4.2% smaller per minor allele of rs7489119 (P = 0.0008; P(ACT) = 0.018) and 1.9% larger per minor allele of rs5933863 (P = 0.013; P(ACT) = 0.025). These individual SNP associations did not reach statistical significance when we further used Bonferroni correction to consider the number of tested genes. The pathway level summary ARTP P value was not statistically significant.
CONCLUSIONS: Data from this longitudinal study of EPT quitters suggest that genetic variation in two hormone metabolism pathway genes, SLCO1B1 and ARSC, may be associated with change in MD after women stop using EPT. Larger longitudinal studies are needed to confirm our findings.

Goričar K, Kovač V, Jazbec J, et al.
Influence of the folate pathway and transporter polymorphisms on methotrexate treatment outcome in osteosarcoma.
Pharmacogenet Genomics. 2014; 24(10):514-21 [PubMed] Related Publications
OBJECTIVES: Osteosarcoma is the most common primary bone malignancy that occurs mostly in adolescents. Treatment protocols usually include multiagent preoperative and postoperative chemotherapy based on methotrexate, cisplatin, doxorubicin and ifosfamide. Despite a favourable prognosis, there are considerable interindividual differences in treatment outcome. Genetic variability of enzymes involved in the metabolism and transport of methotrexate could contribute towards observed differences in response to chemotherapy. Our aim was to evaluate how polymorphisms in the folate pathway and transporter genes influence treatment outcome in osteosarcoma patients.
PATIENTS AND METHODS: In total, 44 osteosarcoma patients treated with methotrexate were genotyped for eleven polymorphisms in four folate pathway and five folate transporter genes. Cox regression was used in survival analysis. Logistic regression was used to assess the influence of polymorphisms on treatment efficacy and toxicity and nonparametric tests were used to determine the influence on serum methotrexate levels.
RESULTS: Polymorphic SLCO1B1 rs4149056 and rs11045879 alleles were associated with significantly higher serum methotrexate area under the curve (P=0.001 and 0.011, respectively). Carriers of at least one polymorphic SLCO1B1 rs4149056 and rs11045879 allele tended to have longer event-free survival compared with patients with two wild-type alleles [P=0.040, hazard ratio (HR)=0.26, 95% confidence interval (CI)=0.07-0.94; and P=0.034, HR=0.20, 95% CI=0.05-0.89, respectively]. Compared with the most common haplotype, carriers of both polymorphic alleles had significantly longer event-free survival (P=0.009, HR=0.27, 95% CI=0.10-0.72).
CONCLUSION: We have shown that SLCO1B1 polymorphisms influence methotrexate disposition and survival in methotrexate-treated osteosarcoma patients and therefore might serve as pharmacogenetic markers of treatment outcome.

Zgheib NK, Akra-Ismail M, Aridi C, et al.
Genetic polymorphisms in candidate genes predict increased toxicity with methotrexate therapy in Lebanese children with acute lymphoblastic leukemia.
Pharmacogenet Genomics. 2014; 24(8):387-96 [PubMed] Related Publications
BACKGROUND: The aim of this study is to analyze polymorphisms in genes involved in 6-mercaptopurine detoxification (TPMT); methotrexate (MTX) metabolism including ABCB1 (or MDR1), ABCC2, SLC19A1 (or RFC1), and SLCO1B1; and the MTX effect mainly MTHFR and TYMS, and to assess whether these polymorphisms are predictors of treatment toxicity and/or MTX clearance.
MATERIALS AND METHODS: This study included 127 Lebanese acute lymphoblastic leukemia patients, of whom 117 were treated following the St Jude's Children Research Hospital protocol. Genotyping was performed using real-time PCR or restriction fragment length polymorphism. MTX levels were measured using a polarization fluorescence assay from Roche. MTX clearance was estimated on the basis of all available MTX levels measured after high-dose MTX treatment during the consolidation phase.
RESULTS: Five variants in four genes (MTHFR, ABCB1, ABCC2, and TYMS) were shown to be associated with toxicity, but neither was associated with MTX pharmacokinetic parameters. For instance, during the consolidation phase, a statistically significant association was found between MTHFR rs1801133 variant allele carriers and a decrease in hemoglobin levels [odds ratio (OR)=3.057; 95% confidence interval (CI): 1.217; 7.680]. In addition, a statistically significant association was found among neutropenia (absolute neutrophil count<500) and variant allele carriers of ABCB1 rs1045642 (OR=5.174; 95% CI: 1.674; 15.989) and ABCB1 rs1128503 (OR=3.364; 95% CI: 1.257; 9.004), respectively. ABCC2 rs717620 variant allele carriers needed significantly more time to reach a MTX level below 0.1 µmol/l (β=5.122; 95% CI: 1.412; 8.831). During the continuation phase, a statistically significant association was found between ABCC2 rs717620 and TYMS 28-bp tandem repeats carriers with the need to decrease weekly MTX doses (β=-4.905; 95% CI: -9; -0.809 and β=-5.770; 95% CI: -10.138; -1.403), respectively.
CONCLUSION: Genotyping for MTHFR, ABCB1, ABCC2, and TYMS polymorphisms may be useful in identifying patients at risk of increased MTX toxicity and the need for dose optimization before treatment initiation.

Csordas K, Lautner-Csorba O, Semsei AF, et al.
Associations of novel genetic variations in the folate-related and ARID5B genes with the pharmacokinetics and toxicity of high-dose methotrexate in paediatric acute lymphoblastic leukaemia.
Br J Haematol. 2014; 166(3):410-20 [PubMed] Related Publications
High-dose methotrexate (HD-MTX) plays an important role in the consolidation therapy of acute lymphoblastic leukaemia (ALL) in many treatment regimens worldwide. However, there is a large interpatient variability in the pharmacokinetics and toxicity of the drug. We investigated the influence of single nucleotide polymorphisms (SNPs) in genes of the folate metabolic pathway, transporter molecules and transcription proteins on the pharmacokinetics and toxicity of MTX and 7-hydroxy-methotrexate (7-OH-MTX). 63 SNPs of 14 genes were genotyped and a total of 463 HD-MTX courses (administered according to the ALL-BFM 95 and ALL IC-BFM 2002 protocols) were analysed. Haematological, hepatic and renal toxicities, estimated by routine laboratory parameters were evaluated. Random forest and regression trees were used for variable selection and model building. Linear mixed models were established to prove the significance of the selected variables. SNPs (rs4948502, rs4948496, rs4948487) of the ARID5B gene were associated with the serum levels of MTX (P < 0·02), serum levels and area under the curve of 7-OH-MTX (P < 0·02) and with hypoproteinaemia (P = 0·004). SLCO1B1 rs4149056 also showed a significant association with serum MTX levels (P < 0·001). Our findings confirm the association of novel genetic variations in folate-related and ARID5B genes with the serum MTX levels and acute toxicity.

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