Gene Summary

Gene:SLCO1B3; solute carrier organic anion transporter family member 1B3
Aliases: LST3, HBLRR, LST-2, OATP8, OATP-8, OATP1B3, SLC21A8, LST-3TM13
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 endogenous and xenobiotic compounds and plays a critical role in bile acid and bilirubin transport. Mutations in this gene are a cause of Rotor type hyperbilirubinemia. [provided by RefSeq, Feb 2012]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:solute carrier organic anion transporter family member 1B3
Source:NCBIAccessed: 10 March, 2017


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 10 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 10 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

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: SLCO1B3 (cancer-related)

Sewda K, Coppola D, Enkemann S, et al.
Cell-surface markers for colon adenoma and adenocarcinoma.
Oncotarget. 2016; 7(14):17773-89 [PubMed] Free Access to Full Article Related Publications
Early detection of colorectal cancer (CRC) is crucial for effective treatment. Among CRC screening techniques, optical colonoscopy is widely considered the gold standard. However, it is a costly and invasive procedure with a low rate of compliance. Our long-term goal is to develop molecular imaging agents for the non-invasive detection of CRC by molecular imaging-based colonoscopy using CT, MRI or fluorescence. To achieve this, cell surface targets must be identified and validated. Here, we report the discovery of cell-surface markers that distinguish CRC from surrounding tissues that could be used as molecular imaging targets. Profiling of mRNA expression microarray data from patient tissues including adenoma, adenocarcinoma, and normal gastrointestinal tissues was used to identify potential CRC specific cell-surface markers. Of the identified markers, six were selected for further validation (CLDN1, GPR56, GRM8, LY6G6D/F, SLCO1B3 and TLR4). Protein expression was confirmed by immunohistochemistry of patient tissues. Except for SLCO1B3, diffuse and low expression was observed for each marker in normal colon tissues. The three markers with the greatest protein overexpression were CLDN1, LY6G6D/F and TLR4, where at least one of these markers was overexpressed in 97% of the CRC samples. GPR56, LY6G6D/F and SLCO1B3 protein expression was significantly correlated with the proximal tumor location and with expression of mismatch repair genes. Marker expression was further validated in CRC cell lines. Hence, three cell-surface markers were discovered that distinguish CRC from surrounding normal tissues. These markers can be used to develop imaging or therapeutic agents targeted to the luminal surface of CRC.

Park HS, Lim SM, Shin HJ, et al.
Pharmacogenetic analysis of advanced non-small-cell lung cancer patients treated with first-line paclitaxel and carboplatin chemotherapy.
Pharmacogenet Genomics. 2016; 26(3):116-25 [PubMed] Related Publications
BACKGROUND: Genetic polymorphisms contribute toward interindividual variations in drug response. We investigated the effects of genetic polymorphisms on the clinical outcome of advanced non-small-cell lung cancer patients with first-line paclitaxel and carboplatin.
MATERIALS AND METHODS: A total of 194 non-small-cell lung cancer patients were prospectively enrolled from January 2010 to January 2013. We genotyped 11 polymorphisms in seven genes involved in the glycolysis pathway and the related pharmacokinetic/pharmacodynamic pathway. Genetic associations with PET-SUV, survival outcome, and toxicity were analyzed, and in-vitro drug transport activity was measured in the oocyte system.
RESULTS: Patients with the c.334 T>G and c.699 G>A homozygous variant in SLCO1B3 showed a higher incidence of grade 3/4 anemia (P=0.002). Transport activities of oocyte that overexpress the SLCO1B3 c.699 G>A variant showed a significantly decreased uptake of paclitaxel compared with the wild-type expressing oocytes. In addition, patients with GG/GA/AA genotypes of ABCB1, c.2677 T>G/A locus showed inferior progression-free survival (hazard ratio=1.49, P=0.017) compared with other genotypes. The GA genotype of HIF1A, c.1834 G>A locus was associated with inferior progression-free survival compared with the GG genotype (hazard ratio=2.47, P=0.008).
CONCLUSION: This study showed that the SLCO1B3 c.699 G>A polymorphism may predict anemia and ABCB1, HIF1A polymorphism are highly predictive for worse survival in advanced NSCLC with first-line paclitaxel and carboplatin.

Dorman SN, Baranova K, Knoll JH, et al.
Genomic signatures for paclitaxel and gemcitabine resistance in breast cancer derived by machine learning.
Mol Oncol. 2016; 10(1):85-100 [PubMed] Related Publications
Increasingly, the effectiveness of adjuvant chemotherapy agents for breast cancer has been related to changes in the genomic profile of tumors. We investigated correspondence between growth inhibitory concentrations of paclitaxel and gemcitabine (GI50) and gene copy number, mutation, and expression first in breast cancer cell lines and then in patients. Genes encoding direct targets of these drugs, metabolizing enzymes, transporters, and those previously associated with chemoresistance to paclitaxel (n = 31 genes) or gemcitabine (n = 18) were analyzed. A multi-factorial, principal component analysis (MFA) indicated expression was the strongest indicator of sensitivity for paclitaxel, and copy number and expression were informative for gemcitabine. The factors were combined using support vector machines (SVM). Expression of 15 genes (ABCC10, BCL2, BCL2L1, BIRC5, BMF, FGF2, FN1, MAP4, MAPT, NFKB2, SLCO1B3, TLR6, TMEM243, TWIST1, and CSAG2) predicted cell line sensitivity to paclitaxel with 82% accuracy. Copy number profiles of 3 genes (ABCC10, NT5C, TYMS) together with expression of 7 genes (ABCB1, ABCC10, CMPK1, DCTD, NME1, RRM1, RRM2B), predicted gemcitabine response with 85% accuracy. Expression and copy number studies of two independent sets of patients with known responses were then analyzed with these models. These included tumor blocks from 21 patients that were treated with both paclitaxel and gemcitabine, and 319 patients on paclitaxel and anthracycline therapy. A new paclitaxel SVM was derived from an 11-gene subset since data for 4 of the original genes was unavailable. The accuracy of this SVM was similar in cell lines and tumor blocks (70-71%). The gemcitabine SVM exhibited 62% prediction accuracy for the tumor blocks due to the presence of samples with poor nucleic acid integrity. Nevertheless, the paclitaxel SVM predicted sensitivity in 84% of patients with no or minimal residual disease.

Furihata T, Sun Y, Chiba K
Cancer-type Organic Anion Transporting Polypeptide 1B3: Current Knowledge of the Gene Structure, Expression Profile, Functional Implications and Future Perspectives.
Curr Drug Metab. 2015; 16(6):474-85 [PubMed] Related Publications
Human organic anion transporting polypeptide 1B3 (OATP1B3) is a hepatocyte drug transporter that facilitates uptake of various therapeutic drugs from the circulatory system. Shortly after its initial identification in the liver, OATP1B3 expression was also reported in various solid cancer tissues. In the years since that time, it has been presumed that the OATP1B3 expressed in cancer tissues is identical to that expressed in the liver. However, we have recently identified a new OATP1B3 mRNA variant in cancer tissues, which we have named cancer-type OATP1B3 (Ct-OATP1B3). Given that the identification of Ct-OAT1B3 as a bona fide cancer-associated isoform revises a longstanding study premise, it is essential to fully elucidate the molecular function of Ct-OATP1B3 in cancer cells. Based on the predicted Ct-OATP1B3 protein structure, it is reasonable to assume that it functions as a transporter, but there are a number of ongoing arguments regarding Ct-OATP1B3 protein expression and its functions. With the above points in mind, this review will summarize current knowledge of Ct-OATP1B3 mRNA expression features in cancer tissues and its proposed, yet currently controversial, functions. Based on that background, our future perspectives related to Ct-OATP1B3 studies will also be presented.

Miura T, Ban D, Tanaka S, et al.
Distinct clinicopathological phenotype of hepatocellular carcinoma with ethoxybenzyl-magnetic resonance imaging hyperintensity: association with gene expression signature.
Am J Surg. 2015; 210(3):561-9 [PubMed] Related Publications
BACKGROUND: Although hepatocellular carcinoma (HCC) is mostly a lower intensity lesion in the hepatobiliary phase on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging, some HCCs were shown as a higher intensity lesion (high HCC). This study aimed to reveal the clinicopathological and biological properties of high HCC.
METHODS: Patients who underwent curative hepatectomy as the first treatment for HCC were included. HCC was defined as high HCC if the ratio between the signal intensity of the HCC and the background liver was greater than or equal to 1.0. We retrospectively performed clinicopathological and global gene expression analyses.
RESULTS: Of the 77 patients, 14 had high HCC. Serum protein induced by vitamin K absence or antagonist II levels in high HCC were lower, and the high HCCs were well differentiated. The 3-year disease-free survival rates in high HCC and low HCC patients were 90% and 54%, respectively (P = .035). Overall survival did not differ significantly. Global gene expression analysis revealed that SLCO1B3 was upregulated in high HCC.
CONCLUSIONS: Clinicopathological analysis revealed low-grade malignancy in high HCCs compared with low HCCs. The expression of SLCO1B3 was key to the hyperintensity in the hepatobiliary phase of ethoxybenzyl-diethylenetriamine pentaacetic acid magnetic resonance imaging.

de Lima LT, Bueno CT, Vivona D, et al.
Relationship between SLCO1B3 and ABCA3 polymorphisms and imatinib response in chronic myeloid leukemia patients.
Hematology. 2015; 20(3):137-42 [PubMed] Related Publications
BACKGROUND: Genetic variations in membrane transporters may contribute to imatinib mesylate (IM) resistance in chronic myeloid leukemia (CML). Objective To investigate the relationship between SLCO1B3, SLCO1A2, and ABCA3 polymorphisms and IM response in CML patients.
METHODS: Patients in chronic phase CML (N = 118) were studied. All patients were treated with a standard dose of IM (400 mg/day) and classified into one of the two groups according to their responses. Major molecular response (MMR) and complete molecular response (CMR) were evaluated. Criteria for response failure were established according to European LeukemiaNet (2009). Analysis of the SLCO1B3 c.334T > G (rs4149117) and c.699G > A (rs7311358), SLCO1A2 c.516A > C (rs11568563) and c.-62-361G > A (rs3764043), and ABCA3 c.1755C > G (rs323043) and c.4548-191C > A (rs150929) polymorphisms was carried out by real-time polymerase chain reaction.
RESULTS: SLCO1A2 and ABCA3 polymorphisms have similar frequencies between responders and non-responders. SLCO1B3 699GG and 344TT genotypes were more frequent in the responder group (63.8%) than in the non-responder group (44.7%, P = 0.042). Furthermore, carriers of 699GA/AA and 334TG/GG genotypes presented a higher probability of not responding to the standard dose of IM (odds ratio: 2.17; 95% confidence interval: 1.02-4.64, P = 0.04). Poor CMR for ABCA3 4548-91C > A was observed in patients with the CC/CA genotype when compared to AA carriers in the responder group (P = 0.014).
CONCLUSIONS: SLCO1B3 699GG and 344TT genotypes are associated with non-response to IM, while ABCA3 4548-91 CC/CA genotypes are related to poor CMR in CML patients treated with standard-dose imatinib.

Ueno A, Masugi Y, Yamazaki K, et al.
OATP1B3 expression is strongly associated with Wnt/β-catenin signalling and represents the transporter of gadoxetic acid in hepatocellular carcinoma.
J Hepatol. 2014; 61(5):1080-7 [PubMed] Related Publications
BACKGROUND & AIMS: In the current era of emerging molecular targeted drugs, it is necessary to identify before treatment the specific subclass to which a tumour belongs. Gadoxetic acid is a liver-specific contrast agent that is preferentially taken up by hepatocytes. Therefore, gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) should provide precise molecular information about hepatocellular carcinomas (HCCs). The aim of this study was to investigate the transporters of gadoxetic acid in HCC comprehensively and to analyse the molecular regulatory mechanism of such transporters.
METHODS: Expression levels of transporters, transcriptional factors and Wnt target genes in clinical samples were examined by quantitative real-time reverse transcription polymerase chain reaction and immunohistochemistry. LiCl treatment of the HCC cell line KYN-2 was conducted in vitro to assess the effects of Wnt signalling activity.
RESULTS: Comprehensive analyses of transporter mRNAs and protein expressions revealed that the organic anion transporting polypeptide 1B3 (OATP1B3) had the strongest correlation with tumour enhancement in hepatobiliary-phase images of EOB-MRI. Association analysis with OATP1B3 expression revealed significant correlation with the expression of Wnt/β-catenin target genes. Further, LiCl treatment induced OATP1B3 mRNA expression in KYN-2 cells, indicating a strong association between OATP1B3 expression and Wnt/β-catenin signalling. The sensitivity and specificity to predict Wnt/β-catenin-activated HCC using tumour enhancement in EOB-MRI were 78.9% and 81.7%, respectively.
CONCLUSIONS: OATP1B3 was confirmed as the most important transporter mediating HCC enhancement in EOB-MRI. OATP1B3 expression showed a strong association with the expression of Wnt/β-catenin target genes, therefore, OATP1B3-upregulated HCC likely represents a specific subclass of Wnt/β-catenin-activated HCC.

Dayal JH, Cole CL, Pourreyron C, et al.
Type VII collagen regulates expression of OATP1B3, promotes front-to-rear polarity and increases structural organisation in 3D spheroid cultures of RDEB tumour keratinocytes.
J Cell Sci. 2014; 127(Pt 4):740-51 [PubMed] Free Access to Full Article Related Publications
Type VII collagen is the main component of anchoring fibrils, structures that are integral to basement membrane homeostasis in skin. Mutations in the gene encoding type VII collagen COL7A1 cause recessive dystrophic epidermolysis bullosa (RDEB) an inherited skin blistering condition complicated by frequent aggressive cutaneous squamous cell carcinoma (cSCC). OATP1B3, which is encoded by the gene SLCO1B3, is a member of the OATP (organic anion transporting polypeptide) superfamily responsible for transporting a wide range of endogenous and xenobiotic compounds. OATP1B3 expression is limited to the liver in healthy tissues, but is frequently detected in multiple cancer types and is reported to be associated with differing clinical outcome. The mechanism and functional significance of tumour-specific expression of OATP1B3 has yet to be determined. Here, we identify SLCO1B3 expression in tumour keratinocytes isolated from RDEB and UV-induced cSCC and demonstrate that SLCO1B3 expression and promoter activity are modulated by type VII collagen. We show that reduction of SLCO1B3 expression upon expression of full-length type VII collagen in RDEB cSCC coincides with acquisition of front-to-rear polarity and increased organisation of 3D spheroid cultures. In addition, we show that type VII collagen positively regulates the abundance of markers implicated in cellular polarity, namely ELMO2, PAR3, E-cadherin, B-catenin, ITGA6 and Ln332.

Ishizawa T, Masuda K, Urano Y, et al.
Mechanistic background and clinical applications of indocyanine green fluorescence imaging of hepatocellular carcinoma.
Ann Surg Oncol. 2014; 21(2):440-8 [PubMed] Related Publications
BACKGROUND: Although clinical applications of intraoperative fluorescence imaging of liver cancer using indocyanine green (ICG) have begun, the mechanistic background of ICG accumulation in the cancerous tissues remains unclear.
METHODS: In 170 patients with hepatocellular carcinoma cells (HCC), the liver surfaces and resected specimens were intraoperatively examined by using a near-infrared fluorescence imaging system after preoperative administration of ICG (0.5 mg/kg i.v.). Microscopic examinations, gene expression profile analysis, and immunohistochemical staining were performed for HCCs, which showed ICG fluorescence in the cancerous tissues (cancerous-type fluorescence), and HCCs showed fluorescence only in the surrounding non-cancerous liver parenchyma (rim-type fluorescence).
RESULTS: ICG fluorescence imaging enabled identification of 273 of 276 (99%) HCCs in the resected specimens. HCCs showed that cancerous-type fluorescence was associated with higher cancer cell differentiation as compared with rim-type HCCs (P < 0.001). Fluorescence microscopy identified the presence of ICG in the canalicular side of the cancer cell cytoplasm, and pseudoglands of the HCCs showed a cancerous-type fluorescence pattern. The ratio of the gene and protein expression levels in the cancerous to non-cancerous tissues for Na(+)/taurocholate cotransporting polypeptide (NTCP) and organic anion-transporting polypeptide 8 (OATP8), which are associated with portal uptake of ICG by hepatocytes that tended to be higher in the HCCs that showed cancerous-type fluorescence than in those that showed rim-type fluorescence.
CONCLUSIONS: Preserved portal uptake of ICG in differentiated HCC cells by NTCP and OATP8 with concomitant biliary excretion disorders causes accumulation of ICG in the cancerous tissues after preoperative intravenous administration. This enables highly sensitive identification of HCC by intraoperative ICG fluorescence imaging.

Gruber C, Koller U, Murauer EM, et al.
The design and optimization of RNA trans-splicing molecules for skin cancer therapy.
Mol Oncol. 2013; 7(6):1056-68 [PubMed] Related Publications
Targeting tumor marker genes by RNA trans-splicing is a promising means to induce tumor cell-specific death. Using a screening system we designed RNA trans-splicing molecules (RTM) specifically binding the pre-mRNA of SLCO1B3, a marker gene in epidermolysis bullosa associated squamous cell carcinoma (EB-SCC). Specific trans-splicing, results in the fusion of the endogenous target mRNA of SLCO1B3 and the coding sequence of the suicide gene, provided by the RTM. SLCO1B3-specific RTMs containing HSV-tk were analyzed regarding their trans-splicing potential in a heterologous context using a SLCO1B3 expressing minigene (SLCO1B3-MG). Expression of the chimeric SLCO1B3-tk was detected by semi-quantitative RT-PCR and Western blot analysis. Cell viability and apoptosis assays confirmed that the RTMs induced suicide gene-mediated apoptosis in SLCO1B3-MG expressing cells. The lead RTM also showed its potential to facilitate a trans-splicing reaction into the endogenous SLCO1B3 pre-mRNA in EB-SCC cells resulting in tk-mediated apoptosis. We assume that the pre-selection of RTMs by our inducible cell-death system accelerates the design of optimal RTMs capable to induce tumor specific cell death in skin cancer cells.

Liu T, Li Q
Organic anion-transporting polypeptides: a novel approach for cancer therapy.
J Drug Target. 2014; 22(1):14-22 [PubMed] Related Publications
Organic anion-transporting polypeptides (OATPs) encoded by the SLCO genes constitute an important transporter superfamily that mediates transmembrane transport of various clinical drugs and endogenous nutrients. Eleven human OATPs with different transport functions are expressed in various tissues. Bile acids, steroid hormone conjugates, prostaglandins, testosterone and thyroid hormones that promote cell proliferation are typical substrates of OATPs. Many important clinical drugs have been identified as substrates of OATP1B1, OATP1B3, OATP2B1 and OATP1A2. Liver-specific OATP1B1 and OATP1B3 as well as testis-specific OATP6A1 are expressed in malignancies and can act as biomarkers for many tumours. Various studies have shown the associations of genetic polymorphisms in OATP genes with the uptake pharmacokinetics of their substrates. Because of their abundant expression in tumours and their high transport activity for many cancer drugs, OATPs should be considered as important therapeutic targets in anti-cancer drug design.

Han S, Kim K, Thakkar N, et al.
Role of hypoxia inducible factor-1α in the regulation of the cancer-specific variant of organic anion transporting polypeptide 1B3 (OATP1B3), in colon and pancreatic cancer.
Biochem Pharmacol. 2013; 86(6):816-23 [PubMed] Related Publications
Organic anion transporting polypeptide 1B3 (OATP1B3) was initially considered to be a liver-specific transporter, mediating the uptake of a variety of endogenous and xenobiotic substances. Over the past decade, several investigations reported that OATP1B3 is also expressed across multiple types of cancers. Only recently, our laboratory and others demonstrated the identity of cancer-specific OATP1B3 variants (csOATP1B3) arising from the use of an alternative transcription initiation site, different from the wildtype (WT) OATP1B3 expressed in the normal liver. However, the mechanisms regulating the expression of csOATP1B3 remained unknown. In our current study, we investigated the role of hypoxia and the involvement of hypoxia inducible factor-1α (HIF-1α) in regulating the transcription of csOATP1B3. Our RT-PCR and immunoblotting results indicated that csOATP1B3, but not WT OATP1B3, can be induced in response to ambient or chemical hypoxia (upon exposure to 1% O₂ or cobalt chloride). Reporter assays with deletion and mutated constructs of the csOATP1B3 promoter revealed a functional hypoxia response element (HRE) located in the proximal upstream region. Constructs harboring the HRE displayed the upregulated reporter gene expression in response to hypoxia, but not when mutated. Electrophoretic mobility shift assays using a biotin-labeled csOATP1B3 promoter HRE probe indicated the binding of HIF-1α, which was blocked by an excess of unlabeled csOATP1B3 probe. Furthermore, siRNA-based knockdown of HIF-1α caused a substantial decrease in the expression level of csOATP1B3. Taken together, these findings demonstrate that the transcription of csOATP1B3 is actively engaged during hypoxia, through a commonly utilized pathway involving HIF-1α.

Fujimoto N, Kubo T, Inatomi H, et al.
Polymorphisms of the androgen transporting gene SLCO2B1 may influence the castration resistance of prostate cancer and the racial differences in response to androgen deprivation.
Prostate Cancer Prostatic Dis. 2013; 16(4):336-40 [PubMed] Related Publications
BACKGROUND: Organic anion-transporting polypeptides (OATPs) encoded by SLCO mediate the cellular uptake of many compounds, including androgens. SLCO1B3 and SLCO2B1 are polymorphic, and single-nucleotide polymorphisms of those genes alter androgen transport efficiency. We aimed to investigate the association between genetic variations in SLCOs and the progression to castration-resistant prostate cancer (CRPC).
METHODS: We studied the progression to CRPC for the SLCO1B3 rs4149117 and SLCO2B1 rs12422149 genotypes in 87 prostate cancer patients who received androgen deprivation therapy (ADT). Data were analyzed using the χ(2) test, Kaplan-Meier survival analysis and Cox proportional hazard model.
RESULTS: SLCO3B1 genotypes were not significantly associated with the time to progression (TTP); however, patients carrying the active androgen transport SLCO2B1 genotype (GG allele) exhibited a median TTP that was 7 months shorter than that of patients with impaired androgen-transporting activity SLCO2B1 polymorphisms (GA/AA alleles) (10.0 vs 17.0 months, P=0.004). Active androgen transport genotypes of SLCO2B1 (GG allele) occurred more frequently in African and Caucasian populations than in Japanese and Han Chinese populations (P<0.001).
CONCLUSIONS: These data suggest that SLCO2B1 rs12422149 variants could provide prognostic value for prostate cancer patients treated with ADT and influence ethnic differences in response to ADT. Active androgen import may be one of the underlying mechanisms of resistance to ADT, and androgen-transporting systems could provide novel biomarkers and targets for CRPC treatment.

Imai S, Kikuchi R, Tsuruya Y, et al.
Epigenetic regulation of organic anion transporting polypeptide 1B3 in cancer cell lines.
Pharm Res. 2013; 30(11):2880-90 [PubMed] Related Publications
PURPOSE: The expression of a multispecific organic anion transporter, OATP1B3/SLCO1B3, is associated with clinical prognosis and survival of cancer cells. The aims of present study were to investigate the involvement of epigenetic regulation in mRNA expression of a cancer-type variant of OATP1B3 (Ct-OATP1B3) in cancer cell lines.
METHODS: The membrane localization and transport functions of Ct-OATP1B3 were investigated in HEK293 cells transiently expressing Ct-OATP1B3. DNA methylation profiles around the transcriptional start site of Ct-OATP1B3 in cancer cell lines were determined. The effects of a DNA methyltransferase inhibitor and siRNA knockdown of methyl-DNA binding proteins (MBDs) on the expression of Ct-OATP1B3 mRNA were investigated.
RESULTS: 5'-RACE identified the TSS of Ct-OATP1B3 in PK-8 cells. Ct-OATP1B3 was localized on the plasma membrane, and showed the transport activities of E217βG, fluvastatin, rifampicin, and Gd-EOB-DTPA. The CpG dinucleotides were hypomethylated in Ct-OATP1B3-positive cell lines (DLD-1, TFK-1, PK-8, and PK-45P) but were hypermethylated in Ct-OATP1B3-negative cell lines (HepG2 and Caco-2). Treatment with a DNA methyltransferase inhibitor and siRNA knockdown of MBD2 significantly increased the expression of Ct-OATP1B3 mRNA in HepG2 and Caco-2.
CONCLUSIONS: Ct-OATP1B3 is capable of transporting its substrates into cancer cells. Its mRNA expression is regulated by DNA methylation-dependent gene silencing involving MBD2.

Ogane N, Yasuda M, Kameda Y, et al.
Prognostic value of organic anion transporting polypeptide 1B3 and copper transporter 1 expression in endometrial cancer patients treated with paclitaxel and carboplatin.
Biomed Res. 2013; 34(3):143-51 [PubMed] Related Publications
Paclitaxel and carboplatin (TC) chemotherapy is an effective and well-tolerated regimen against advanced endometrial cancer. Organic anion transporting polypeptide 1B3 (OATP1B3) and copper transporter 1 (CTR1) are critical for the uptake of paclitaxel and carboplatin, respectively. This study aimed to address the prognostic impact of OATP1B3 and CTR1 in endometrial cancer patients treated with adjuvant TC chemotherapy. We immunohistochemically evaluated the expressions of OATP1B3 and CTR1 in 47 stage III endometrial cancers. The high expression levels of OATP1B3 were significantly correlated with type I tumor (P = 0.0005). In univariate analysis, high expression levels of OATP1B3 (P = 0.047) and CTR1 (P = 0.009) were significantly associated with longer disease-free survival (DFS) and longer overall survival (OS), respectively. The patients with tumors showing high expression levels of at least one of OATP1B3 and CTR1 had potentially longer DFS (P = 0.058) and significantly longer OS (P = 0.003) sin the univariate analysis. Combined OATP1B3/CTR1 expression was the sole independent prognostic factor for longer OS in the multivariate analysis (P = 0.013). Our findings suggest that combined OATP1B3/CTR1 expression is a possible predictive/prognostic factor for a good outcome in stage III endometrial cancer patients treated with adjuvant TC chemotherapy.

Lancaster CS, Sprowl JA, Walker AL, et al.
Modulation of OATP1B-type transporter function alters cellular uptake and disposition of platinum chemotherapeutics.
Mol Cancer Ther. 2013; 12(8):1537-44 [PubMed] Free Access to Full Article Related Publications
Expression of the human organic anion transporting polypeptides OATP1B1 and OATP1B3 has been previously believed to be restricted to hepatocytes. Here we show that the gene encoding OATP1B3, but not OATP1B1, is abundantly expressed in multiple human solid tumors that include hepatocellular, lung, and ovarian carcinomas. Surprisingly, OATP1B3 gene expression in a panel of 60 human tumor cell lines was linked with sensitivity to multiple cytotoxic agents, including the platinum anticancer drugs cisplatin, carboplatin, and oxaliplatin. In addition, overexpression of OATP1B3 in mammalian cells increased cellular accumulation of platinum agents and decreased cell survival. In mice with a targeted disruption of the ortholog transporter Oatp1b2, the liver-to-plasma ratio of cisplatin was significantly reduced compared with wild-type mice, without concurrent changes in expression profiles of other transporter genes. Our findings indicate an unexpected role for tumoral and host OATP1B-type carriers in the toxicity and disposition of platinum anticancer drugs, and may provide a foundation for understanding the extensive interindividual pharmacodynamic variability seen with these drugs in patients.

Bedewy AM, El-Maghraby SM
Do SLCO1B3 (T334G) and CYP3A5*3 polymorphisms affect response in Egyptian chronic myeloid leukemia patients receiving imatinib therapy?
Hematology. 2013; 18(4):211-6 [PubMed] Related Publications
BACKGROUND: Imatinib has so far been the first-choice treatment in chronic myeloid leukemia (CML) with excellent results. However, only a proportion of patients achieve major molecular response. Hence, the need to find whether there are some factors that affect the response to treatment is essential. This study aimed to investigate the allele and genotype frequencies of single nucleotide polymorphisms (SNPs) of SLCO1B3 (T334G) and CYP3A5*3 in CML patients undergoing imatinib treatment and to determine whether SNPs of these two genes could predict the response of imatinib therapy in CML patients.
SUBJECTS AND METHODS: We investigated SLCO1B3 (T334G) and CYP3A5*3 polymorphisms by Polymerase Chain Reaction-restriction fragment length polymorphism in 86 Philadelphia positive newly diagnosed Egyptian CML patients (78 patients in chronic phase and 8 patients in accelerated phase). All patients received imatinib therapy and were followed for at least one and half years. The response to imatinib therapy was evaluated by recording the hematological response, cytogenetic response, and molecular response according to the European Leukemia Net criteria.
RESULTS: This study included 86 Philadelphia positive newly diagnosed CML patients, 78 in the early chronic phase and 8 in the accelerated phase. In the chronic phase patients, no association between SLCO1B3 (T334G) exon 3 polymorphism and response to imatinib therapy was detected (P = 0.938) while CYP3A5*3 gene polymorphism was associated with inferior outcome (P < 0.001). In the group of accelerated phase patients, the SLCO1B3 polymorphic variants (TG) and (GG) were detected equally with none of the patients in this group having the homozygous wild form (TT). The homozygous state for the CYP3A5*3 allele was the most frequent (50%) and the homozygous state for the CYP3A5*1 allele was the least frequent (12.5%) in this group.
CONCLUSION: CYP3A5*3 polymorphism was associated with imatinib efficacy while the SNP SLCO1B3 (T334G) was not associated with the response to imatinib treatment in Egyptian patients with CML in chronic phase. These results prompt us to explore the effect of CYP3A5*3 in CML patients taking imatinib in a larger scale study.

Ramachandran A, Betts G, Bhana S, et al.
An in vivo hypoxia metagene identifies the novel hypoxia inducible factor target gene SLCO1B3.
Eur J Cancer. 2013; 49(7):1741-51 [PubMed] Related Publications
A hypoxia-associated gene signature (metagene) was previously derived via in vivo data-mining. In this study, we aimed to investigate whether this approach could identify novel hypoxia regulated genes. From an initial list of nine genes, three were selected for further study (BCAR1, IGF2BP2 and SLCO1B3). Ten cell lines were exposed to hypoxia and interrogated for the expression of the three genes. All three genes were hypoxia inducible in at least one of the 10 cell lines with SLCO1B3 induced in seven. SLCO1B3 was studied further using chromatin immunoprecipitation and luciferase assays to investigate hypoxia inducible factor (HIF) dependent transcription. Two functional HIF response elements were identified within intron 1 of the gene. The functional importance of SLCO1B3 was studied by gene knockdown experiments followed by cell growth assays, flow cytometry and Western blotting. SLCO1B3 knockdown reduced cell size and 3-dimensional spheroid volume, which was associated with decreased activation of the mammalian target of rapamycin (mTOR) pathway. Finally, Oncomine analysis revealed that head and neck and colorectal tumours had higher levels of SLCO1B3 compared to normal tissue. Thus, the knowledge based approach for deriving gene signatures can identify novel biologically relevant genes.

Hays A, Apte U, Hagenbuch B
Organic anion transporting polypeptides expressed in pancreatic cancer may serve as potential diagnostic markers and therapeutic targets for early stage adenocarcinomas.
Pharm Res. 2013; 30(9):2260-9 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Organic Anion Transporting Polypeptides (OATPs) are expressed in various epithelial tissues in the body. Because they can be expressed in cancers and because they can transport anticancer drugs, OATPs could be potential targets for cancer therapy. Therefore we examined their expression in human pancreatic ductal adenocarcinomas.
METHODS: Expression of all 11 human OATPs was measured at the mRNA level and OATPs with highest expression were characterized at the protein level.
RESULTS: Transcripts of SLCO1B3, SLCO2A1, SLCO3A1 and SLCO4A1 were detected in all the tested pancreatic tissues. OATP1B3, OATP2A1, OATP3A1 and OATP4A1 protein expression was confirmed in these tissues and expression of all four transporters increased in pancreatic adenocarcinoma compared to normal pancreas. OATP1B3 expression was highest in pancreatic hyperplasia and stage one adenocarcinomas compared to stage two and three adenocarcinomas.
CONCLUSION: OATP1B3, OATP2A1, OATP3A1 and OATP4A1 are up-regulated in pancreatic adenocarcinoma and could potentially be used to target anticancer drugs to pancreatic cancer. Additionally, because expression of OATP1B3 is highest in pancreatitis and stage one adenocarcinoma, which leads to pancreatic cancer, OATP1B3 is a potential marker to diagnose patients with early stage pancreatic adenocarcinomas.

Fesenko EE, Heydarov RN, Stepanova EV, et al.
Microarray with LNA-probes for genotyping of polymorphic variants of Gilbert's syndrome gene UGT1A1(TA)n.
Clin Chem Lab Med. 2013; 51(6):1177-84 [PubMed] Related Publications
BACKGROUND: Gilbert's syndrome is a common metabolic dysfunction characterized by elevated levels of unconjugated bilirubin in the bloodstream. This condition is usually caused by additional (TA) insertions in a promoter region of the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene, which instead of the sequence А(TА)6TАА contains А(TА)7TАА. While the condition itself is benign, it presents elevated risk for patients treated with irinotecan, a common chemotherapy drug.
METHODS: The technique is based on hybridization analysis of a pre-amplified segment of the UGT1A1 gene promoter performed on a microarray. Specific probes containing locked nucleic acids (LNA) were designed and immobilized on the microarray to provide accurate identification.
RESULTS: A microarray has been developed to identify both common and rare variants of UGT1A1(TA)n polymorphisms. In total, 108 individuals were genotyped. Out of these, 47 (43.5%) had homozygous wild-type genotypes (TA)6/(TA)6; 41(38%) were heterozygotes (TA)6/(TA)7; and 18 (16.7%)--homozygotes (TA)7/(TA)7. In two cases (1.8%), rare genotypes (TA)5/(TA)7 and (TA)5/(TA)6 were found. The results were in full agreement with the sequencing. In addition, synthetic fragments corresponding to all human allelic variants [(TA)5, (TA)6, (TA)7, (TA)8] were successfully tested.
CONCLUSIONS: The developed microarray-based approach for identification of polymorphic variants of the UGT1A1 gene is a promising and reliable diagnostic tool that can be successfully implemented in clinical practice.

Lopez-Lopez E, Ballesteros J, Piñan MA, et al.
Polymorphisms in the methotrexate transport pathway: a new tool for MTX plasma level prediction in pediatric acute lymphoblastic leukemia.
Pharmacogenet Genomics. 2013; 23(2):53-61 [PubMed] Related Publications
OBJECTIVES: Methotrexate (MTX) is an important component of therapy for pediatric acute lymphoblastic leukemia (ALL). Treatment with MTX often causes toxicity, which can necessitate dose reduction or treatment cessation. Interindividual differences in adverse reactions can be due to different factors, including polymorphisms in key genes. Recently, we confirmed the association between SLCO1B1 rs11045879 polymorphism and toxicity previously proposed by Treviño and colleagues. As SLCO1B1 is a transporter involved in MTX elimination, other polymorphisms in genes from this pathway could also have a role in MTX toxicity. The aim of the present study was to analyze in depth the role of polymorphisms in the genes of the MTX transport pathway as putative toxicity predictors in pediatric ALL.
METHODS: We analyzed 384 single nucleotide polymorphisms in 12 transporter genes (SLCO1B1, SLCO1B3, SLCO1A2, ABCB1, ABCG2, ABCC1, ABCC2, ABCC3, ABCC4, SLC19A1, SLC22A6 and SLC22A8) and their correlation with different toxicity parameters in 151 pediatric ALL patients treated using the LAL/SHOP protocol.
RESULTS: A significant association with MTX plasma levels was found for 21 polymorphisms from seven genes and 15 haplotypes. After correction, rs9516519 in ABCC4, rs3740065 in ABCC2, and haplotype GCGGG in ABCC2 remained significantly associated.
CONCLUSION: Our results suggest that polymorphisms in ABCC4 and ABCC2 could be novel markers for MTX toxicity in pediatric ALL.

Jabir RS, Naidu R, Annuar MA, et al.
Pharmacogenetics of taxanes: impact of gene polymorphisms of drug transporters on pharmacokinetics and toxicity.
Pharmacogenomics. 2012; 13(16):1979-88 [PubMed] Related Publications
Interindividual variability in drug response and the emergence of adverse drug effects are the main causes of treatment failure in cancer therapy. Functional membrane drug transporters play important roles in altering pharmacokinetic profile, resistance to treatment, toxicity and patient survival. Pharmacogenetic studies of these transporters are expected to provide new approaches for optimizing therapy. Taxanes are approved for the treatment of various cancers. Circulating taxanes are taken up by SLCO1B3 into hepatocytes. The CYP450 enzymes CYP3A4, CYP3A5 and CYP2C8 are responsible for the conversion of taxanes into their metabolites. Ultimately, ABCB1 and ABCC2 will dispose the metabolites into bile canaliculi. Polymorphisms of genes encoding for proteins involved in the transport and clearance of taxanes reduce excretion of the drugs, leading to development of toxicity in patients. This review addresses current knowledge on genetic variations of transporters affecting taxanes pharmacokinetics and toxicity, and provides insights into future direction for personalized medicine.

Thakkar N, Kim K, Jang ER, et al.
A cancer-specific variant of the SLCO1B3 gene encodes a novel human organic anion transporting polypeptide 1B3 (OATP1B3) localized mainly in the cytoplasm of colon and pancreatic cancer cells.
Mol Pharm. 2013; 10(1):406-16 [PubMed] Related Publications
OATP1B3 is a member of the OATP (organic anion transporting polypeptides) superfamily, responsible for mediating the transport of numerous endogenous and xenobiotic substances. Although initially reported to be exclusively expressed in the liver, several studies reported that OATP1B3 is frequently expressed in multiple types of cancers and may be associated with differing clinical outcomes. However, a detailed investigation on the expression and function of OATP1B3 protein in cancer has been lacking. In this study, we confirmed that colon and pancreatic cancer cells express variant forms of OATP1B3, different from OATP1B3 wild-type (WT) expressed in the normal liver. OATP1B3 variant 1 (V1), the most prevalent form among the variants, contains alternative exonic sequences (exon 2a) instead of exons 1 and 2 present in OATP1B3 WT. The translated product of OATP1B3 V1 is almost identical to OATP1B3 WT, with exception to the first 28 amino acids at the N-terminus. Exogenous expression of OATP1B3 V1 revealed that OATP1B3 V1 undergoes post-translational modifications and proteasomal degradation to a differing extent compared to OATP1B3 WT. OATP1B3 V1 showed only modest transport activity toward cholecystokin-8 (CCK-8, a prototype OATP1B3 substrate) in contrast to OATP1B3 WT showing a markedly efficient uptake of CCK-8. Consistent with these results, OATP1B3 V1 was localized mainly in the cytoplasm with a much lower extent of trafficking to the surface membrane compared to OATP1B3 WT. In summary, our results demonstrate that colon and pancreatic cancer cells express variant forms of OATP1B3 with only limited transport activity and different subcellular localization compared to OATP1B3 WT. These observed differences at the molecular and functional levels will be important considerations for further investigations of the biological and clinical significance of OATP1B3 expression in cancer.

Lewis LD, Miller AA, Owzar K, et al.
The relationship of polymorphisms in ABCC2 and SLCO1B3 with docetaxel pharmacokinetics and neutropenia: CALGB 60805 (Alliance).
Pharmacogenet Genomics. 2013; 23(1):29-33 [PubMed] Free Access to Full Article Related Publications
Docetaxel-related neutropenia was associated with polymorphisms in the drug transporters ABCC2 and SLCO1B3 in Japanese cancer patients. We hypothesized that this association is because of reduced docetaxel clearance, associated with polymorphisms in those genes. We studied 64 US cancer patients who received a single cycle of 75 mg/m of docetaxel monotherapy. We found that the ABCC2 polymorphism at rs-12762549 trended to show a relationship with reduced docetaxel clearance (P=0.048), but not with neutropenia. There was no significant association of the SLCO1B3 polymorphisms with docetaxel clearance or neutropenia. We conclude that the relationship between docetaxel-associated neutropenia and polymorphisms in drug transporters identified in Japanese patients was not confirmed in this cohort of US cancer patients.

Zolk O, Schnepf R, Muschler M, et al.
Transporter gene expression in human head and neck squamous cell carcinoma and associated epigenetic regulatory mechanisms.
Am J Pathol. 2013; 182(1):234-43 [PubMed] Related Publications
Expression levels of membrane transporters may affect the disposition, and thereby treatment efficacy, of anticancer drugs in human head and neck squamous cell carcinoma (HNSCC). Herein, we analyzed the gene expression profile of membrane transporters in HNSCC. In addition, we evaluated the mechanisms of transporter regulation in HNSCC and focused on the role of the nuclear pregnane X receptor (or NR1I2) and epigenetic mechanisms. Real-time RT-PCR revealed a significantly increased mRNA expression of membrane transporters SLCO1A2 and SLCO1B3 and a significantly decreased expression of transporters SLCO2B1, SLCO2A1, and ABCC3 in human HNSCC tumors compared with adjacent normal mucosa. An association between SLCO2B1 mRNA levels in tumors and 5-year survival of patients with HNSCC was observed (χ2 = 6.59, P = 0.010). Bisulfite sequencing revealed that promoter CpG islands of ABCC3 and SLCO2A1 were not hypermethylated, indicating that these genes were not epigenetically silenced in HNSCC tumors. In HNSCC-derived cell lines, transcript expression of transporters (e.g., ABCC3 or SLCO2A1; P < 0.001 for both) and NR1I2 (P < 0.001) was markedly induced by the DNA methyltransferase inhibitor, decitabine. Cotreatment with the prototypical pregnane X receptor activator, rifampicin, significantly reversed decitabine-induced ABCC3 and SLCO2A1 expression. In summary, the expression of drug transporters (i) is markedly changed in HNSCC tumor tissues compared with normal mucosa, (ii) might be predictive of the outcome of patients with HNSCC, and (iii) is affected by novel epigenetic therapies and is further modulated by nuclear receptor-mediated mechanisms.

Banerjee N, Allen C, Bendayan R
Differential role of organic anion-transporting polypeptides in estrone-3-sulphate uptake by breast epithelial cells and breast cancer cells.
J Pharmacol Exp Ther. 2012; 342(2):510-9 [PubMed] Related Publications
The purpose of this study was to investigate the differential expression and function of organic anion-transporting polypeptides (OATPs) in breast epithelial and breast cancer cells. Estrone-3-sulfate (E3S), a substrate for 7 of 11 OATPs, is a predominant source of tumor estrogen in postmenopausal, hormone-dependent patients with breast cancer. Overexpression of certain OATPs (e.g., OATP1A2) reported in breast tumor tissues compared with surrounding normal tissues could contribute toward two to three times higher tumoral E3S concentration. Little is known about expression and function of other OATP family members among breast epithelial and breast cancer cells. We therefore compared gene and protein expression of seven OATPs (OATP1A2, OATP1B1, OATP1B3, OATP1C1, OATP2B1, OATP3A1, and OATP4A1) in immortalized breast epithelial cells (MCF10A), hormone-dependent breast cancer cells (MCF7), and hormone-independent breast cancer cells (MDA/LCC6-435, MDA-MB-231, and MDA-MB-468) by quantitative polymerase chain reaction and immunoblotting, respectively. Expression of solute carrier superfamily encoding for OATPs (SLCO) 1A2, 1B1, 1B3, 2B1, and 3A1 is exclusive, similar, or significantly higher in cancer cells compared with MCF10A cells. Protein expression of OATPs is found to be either exclusive or higher in cancer cells compared with MCF10A cells. Specificity of OATP-mediated E3S uptake is observed only in cancer cells, with the highest total uptake in MCF7 cells. Transport kinetics of E3S uptake demonstrates transport efficiency that is 10 times greater in the MCF7 cells than in the hormone-independent cells. These data suggest that OATPs could be a novel therapeutic target for hormone-dependent breast cancers, particularly in postmenopausal patients, where the major source of tumor estrogen is E3S.

Gil J, Sąsiadek MM
Gilbert syndrome: the UGT1A1*28 promoter polymorphism as a biomarker of multifactorial diseases and drug metabolism.
Biomark Med. 2012; 6(2):223-30 [PubMed] Related Publications
Gilbert syndrome belongs to the group of the most common human metabolic disorders and is characterized by an elevated level of bilirubin in blood serum. A polymorphism of the 5´ end of the UGT1A1 gene promoter, a homozygous insertion of TA pairs (genotype UGT1A1*28/*28), results in a decrease in bilirubin glucuronidation activity and therefore leads to an increase in the level of unconjugated bilirubin (hyperbilirubinemia). Genotyping the UGT1A1 promoter is an important step in the determination of the etiology of free hyperbilirubinemia of unknown origin. Molecular diagnosis enables avoiding invasive diagnostic procedures, such as liver biopsy, in establishing the appropriate diagnosis and prognosis, as well as in establishing the correct therapeutic procedures in a variety of diseases (e.g., chemotherapy or bone marrow transplantation). Moreover, the UGT1A1*28/*28 genotype has emerged as an important element in drug tolerance, as well as in multifactorial diseases, such as cancer. However, the role of this polymorphism is still not completely understood. In this review we have summarized current knowledge and attempted to propose directions for further research.

Nagai M, Furihata T, Matsumoto S, et al.
Identification of a new organic anion transporting polypeptide 1B3 mRNA isoform primarily expressed in human cancerous tissues and cells.
Biochem Biophys Res Commun. 2012; 418(4):818-23 [PubMed] Related Publications
Organic anion transporting polypeptide 1B3 (OATP1B3) is a hepatocyte plasma membrane protein that transports various endogenous and xenobiotic compounds. Although it is exclusively expressed in the human liver under normal conditions, OATP1B3 can be also expressed in various human cancer tissues that have been associated with prognosis and clinical outcomes. However, despite the potential significance of the latter finding, no experimental evidence addressing the molecular entity of cancer-associated OATP1B3 has been provided to date. In this paper, we report the identification of a new OATP1B3 mRNA isoform expressed in human colon and lung cancer tissues, which we named cancer-type OATP1B3 (Ct-OATP1B3). Our results also make known a previously unidentified transcription start site and an alternative promoter region, localized at intron 2, from which Ct-OATP1B3 mRNA is generated. Isoform specific mRNA quantification showed that the Ct-OATP1B3 mRNA level was strikingly higher than that of Lt-OATP1B3 mRNA in human cancer tissues. In addition, the results showed that the translation occurred at three out of four open reading frames. To summarize, our results clearly demonstrate that the newly-identified Ct-OATP1B3 (but not Lt-OATP1B3) is the primary mRNA isoform, at least in the human cancerous samples we have examined. In line with the possibility that its translation products play important biological roles in cancer cells, we strongly believe that the existence of Ct-OATP1B3 should be taken into account during future studies of OATP1B3 associated with cancer prognosis and clinical outcomes.

Kim KP, Ahn JH, Kim SB, et al.
Prospective evaluation of the drug-metabolizing enzyme polymorphisms and toxicity profile of docetaxel in Korean patients with operable lymph node-positive breast cancer receiving adjuvant chemotherapy.
Cancer Chemother Pharmacol. 2012; 69(5):1221-7 [PubMed] Related Publications
BACKGROUND: Inter-individual variability of pharmacokinetics may account for unpredictable toxicities of docetaxel.
METHODS: From March 2007 to June 2008, female patients with operable lymph node-positive breast cancer receiving docetaxel-containing adjuvant chemotherapy were included in this study. The 4 cycles of planned dose of docetaxel (100 mg/m(2)) was performed as adjuvant chemotherapy, following 4 cycles of adriamycin and cyclophosphamide. We evaluated toxicity profile of docetaxel and single nucleotide polymorphisms (SNPs) of CYP3A5 gene, ABCB1 gene, ABCC2 gene and SCLO1B3 gene. Toxicities during treatment of docetaxel were evaluated and defined according to the NCI CTCAE version 3.0.
RESULTS: Pharmacogenetic analysis was performed in 218 Korean women who had received the uniformly planned chemotherapy. With regard to ABCB1 3435 C>T, ABCB1 3435 T/T had significantly higher risks of neutropenia (P = 0.015). Meanwhile, allele frequencies for CYP3A5 6986 G and ABCB1 3435 T revealed a trend for neutropenia (P = 0.107 and 0.068). We could not find any other association between genotypes and other toxicities.
DISCUSSION: Although ABCB1 3435 T/T was significantly associated with docetaxel-related neutropenia in our study population, polymorphism of pharmacogenetic genes related to docetaxel metabolism did not appear to be evidently associated with docetaxel-related adverse events.

Chew SC, Sandanaraj E, Singh O, et al.
Influence of SLCO1B3 haplotype-tag SNPs on docetaxel disposition in Chinese nasopharyngeal cancer patients.
Br J Clin Pharmacol. 2012; 73(4):606-18 [PubMed] Free Access to Full Article Related Publications
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: SLCO1B3 is an influx transporter located at the hepatocyte basolateral membrane and it is involved in the uptake of a broad range of drug substrates including docetaxel. The pharmacogenetics of SLCO1B3 is not well characterized and previous in vivo and in vitro studies reported conflicting results with regards to the functional effects of the limited number of SLCO1B3 polymorphisms that were studied. Docetaxel displays a wide interindividual variability in its pharmacokinetics and pharmacodynamics and an understanding of SLCO1B3 pharmacogenetics might provide clinical benefits in guiding docetaxel dosing.
WHAT THIS STUDY ADDS: The SLCO1B3 gene was comprehensively screened in the local healthy Asian populations (n= 168). A strong linkage disequilibrium pattern was detected across a total of 88 polymorphisms and 15 haplotype-tag SNPs (htSNPs) were identified. These htSNPs were profiled in a cohort of Chinese nasopharyngeal cancer (NPC) patients (n= 50). Genotypic-phenotypic analysis showed that a haplotypic construct comprising of four variants [IVS4+76G>A, 699G>A(Met233Ile), IVS12-5676A>G, and *347_*348insA] was the critical determinant of docetaxel disposition. This study suggests that the comprehensive screening and haplotypic linkage analysis of SLCO1B3 can better elucidate its pharmacogenetic effects on interpatient variability of docetaxel and other putative drug substrates. Further studies are warranted in cancer patients belonging to other ethnic groups. AIMS To completely screen the SLCO1B3 gene in three distinct healthy Asian populations (Chinese, Malay and Indian, n= 168) and investigate the influence of haplotype-tag SNPs (htSNPs) on docetaxel disposition in 50 nasopharyngeal carcinoma patients.
METHODS: Genomic DNA of individuals was screened for SLCO1B3 polymorphisms by direct sequencing. htSNPs were derived based on the sequence clustering algorithm and profiled in the patients. Population based genetic association analysis was performed using Haplostats package implemented in R and PLINK.
RESULTS: A strong linkage disequilibrium pattern was detected across a total of 88 polymorphisms and 15-htSNPs were identified. The SLCO1B3 haplotypic region comprising seven htSNPs was found to be significantly associated with docetaxel clearance (P= 0.003). Conditional haplotype analyses revealed that the haplotypic constructs comprising the IVS4+76G>A, 699G>A(Met233Ile), IVS12-5676A>G, and *347_*348insA polymorphisms were critical determinants of variability in docetaxel disposition [clearance and area under the plasma concentration-time curve (AUC(0,∞)): r(2) = 29% and 22%, respectively]. Patients harbouring the GAG*347insA haplotype were significantly associated with a 30% decrease in clearance and a 40% increase in AUC(0,∞) of docetaxel compared with patients harbouring the reference haplotype, GGA*347wt (P= 0.025 and 0.018, respectively). In contrast, a 50% higher clearance was observed in patients carrying the GAG*347wt haplotype compared with those with the reference haplotype (P= 0.002). The functional SLCO1B3 haplotypic constructs included the widely studied Met233Ile variant and *347_*348insA located in the putative miR-890 binding site in the 3'-untranslated region which may influence the transport characteristics of SLCO1B3.
CONCLUSIONS: This study highlights the importance of SLCO1B3 polymorphic variations in influencing docetaxel disposition in nasopharyngeal carcinoma patients.

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