Effect of OATP1B1 genetic polymorphism on the uptake of tamoxifen and its metabolite, endoxifen

Gao, Chunmei; Pu, Zhichen; He, Chunyuan; Liang, Dahu; Jia, Yuanwei; Yuan, Xiaolong; Wang, Guangji; Xie, Haiyang

doi:10.3892/or.2017.5727

Cited by 16 publications

(20 citation statements)

References 23 publications

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“…4). We find that tamoxifen, which was reported to be a substrate of OATP1B1 (Gao et al 2017), shows high affinity interaction with OATP2B1 (Table S5). This drug is of special interest since it is commonly used for the treatment of ER-positive breast cancer and the facilitated uptake of tamoxifen into cancer cells by uptake transporters can, therefore, possess an advantage.…”

Section: Discussionmentioning

confidence: 62%

Identification of anticancer OATP2B1 substrates by an in vitro triple-fluorescence-based cytotoxicity screen

et al. 2019

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Membrane transporters play an important role in the absorption, distribution, metabolism and excretion of drugs. The cellular accumulation of many drugs is the result of the net function of efflux and influx transporters. Efflux transporters such as P-glycoprotein/ABCB1 have been shown to confer multidrug resistance in cancer. Although expression of uptake transporters has been confirmed in cancer cells, their role in chemotherapy response has not been systematically investigated. In the present study we have adapted a fluorescence-based cytotoxic assay to characterize the influence of key drug-transporters on the toxicity of approved anticancer drugs. Co-cultures of fluorescently labeled parental and transporter-expressing cells (expressing ABCB1, ABCG2 or OATP2B1) were screened against 101 FDA-approved anticancer drugs, using a novel, automated, triple fluorescence-based cytotoxicity assay. By measuring the survival of parental and transporter-expressing cells in co-cultures, we identify those FDA-approved anticancer drugs, whose toxicity is influenced by ABCB1, ABCG2 or OATP2B1. In addition to confirming known substrates of ABCB1 and ABCG2, the fluorescence-based cytotoxicity assays identified anticancer agents whose toxicity was increased in OATP2B1 expressing cells. Interaction of these compounds with OATP2B1 was verified in dedicated transport assays using cell-impermeant fluorescent substrates. Understanding drug-transporter interactions is needed to increase the efficacy of chemotherapeutic agents. Our results highlight the potential of the fluorescence-based HT screening system for identifying transporter substrates, opening the way for the design of therapeutic approaches based on the inhibition or even the exploitation of transporters in cancer cells. Electronic supplementary material The online version of this article (10.1007/s00204-019-02417-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 62%

Identification of anticancer OATP2B1 substrates by an in vitro triple-fluorescence-based cytotoxicity screen

et al. 2019

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“…It has 2 single nucleotide polymorphisms, 388 A > G (63% mutation frequency in Asian populations) and 521 T > C (16% mutation frequency in Asian populations) 10 , forming four haplotypes, OATP1B1*1a (c.388APc.521 T), OATP1B1*1b (c.388GPc.521 T), OABP1B1*5 (c.388APc.521 C) and OATP1B1*15 (c.388GPc.521 C) 11 . Lots of in vitro and in vivo studies have revealed that point mutations in OATP1B1*5 and OATP1B1*15 have vital impacts on OATP1B1 transporter activity and have a significant effect on drug transport 12 – 14 . Nozawa T also reported the genetic polymorphisms could significantly alter the transporting activities of OATP1B1 15 .…”

Section: Introductionmentioning

confidence: 99%

CYP2C9 and OATP1B1 genetic polymorphisms affect the metabolism and transport of glimepiride and gliclazide

Yang

Xiong

Liu

et al. 2018

Sci Rep

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The therapeutic use of glimepiride and gliclazide shows substantial inter-individual variation in pharmacokinetics and pharmacodynamics in human populations, which might be caused by genetic differences among individuals. The aim of this study was to assess the effect of CYP2C9 and OATP1B1 genetic polymorphisms on the metabolism and transport of glimepiride and gliclazide. The uptake of glimepiride and gliclazide was measured in OATP1B1*1a, *5 and *15-HEK293T cells, and their metabolism was measured using CYP2C9*1, *2 and *3 recombinase by LC-MS. Glimepiride in OATP1B1*1a, *5 and *15-HEK293T cells had Vmax values of 155 ± 18.7, 80 ± 9.6, and 84.5 ± 8.2 pmol/min/mg, while gliclazide had Vmax values of 15.7 ± 4.6, 7.2 ± 2.5, and 8.7 ± 2.4 pmol/min/mg, respectively. The clearance of glimepiride and gliclazide in OATP1B1*5 and *15 was significantly reduced compared to the wild-type. Glimepiride in the presence of CYP2C9*1, *2 and *3 recombinase had Vmax values of 21.58 ± 7.78, 15.69 ± 5.59, and 9.17 ± 3.03 nmol/min/mg protein, while gliclazide had Vmax values of 15.73 ± 3.11, 10.53 ± 4.06, and 6.21 ± 2.94 nmol/min/mg protein, respectively. The clearance of glimepiride and gliclazide in CYP2C9*2 and *3 was significantly reduced compared to the wild-type. These findings collectively indicate that OATP1B1*5 and *15 and CYP2C9*2 and *3 have a significant effect on the transport and metabolism of glimepiride and gliclazide.

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“…SLCO1B1 encodes the organic anion-transporter polypeptide 1B1 (OATP1B1), an influx transporter on the sinusoidal membrane of hepatocytes [31]. OATP1B1 transports tamoxifen and endoxifen [32], but our results found that decreased SLCO1B1 activity is associated with higher 4-OHtam levels. This may indicate that 4-OHtam is also transported by OATP1B1, though this has not been studied to our knowledge.…”

Section: Discussionmentioning

confidence: 57%

Effect of Genetic Variability in 20 Pharmacogenes on Concentrations of Tamoxifen and Its Metabolites

Chen

Marcath

Eliassen

et al. 2021

JPM

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Background: Tamoxifen, as a treatment of estrogen receptor positive (ER+) breast cancer, is a weak anti-estrogen that requires metabolic activation to form metabolites with higher anti-estrogenic activity. Endoxifen is the most-studied active tamoxifen metabolite, and endoxifen concentrations are highly associated with CYP2D6 activity. Associations of tamoxifen efficacy with measured or CYP2D6-predicted endoxifen concentrations have been inconclusive. Another active metabolite, 4-OHtam, and other, less active metabolites, Z-4′-endoxifen and Z-4′-OHtam, have also been reported to be associated with tamoxifen efficacy. Method: Genotype for 20 pharmacogenes was determined by VeriDose® Core Panel and VeriDose®CYP2D6 CNV Panel, followed by translation to metabolic activity phenotype following standard activity scoring. Concentrations of tamoxifen and seven metabolites were measured by UPLC-MS/MS in serum samples collected from patients receiving 20 mg tamoxifen per day. Metabolic activity was tested for association with tamoxifen and its metabolites using linear regression with adjustment for upstream metabolites to identify genes associated with each step in the tamoxifen metabolism pathway. Results: A total of 187 patients with genetic and tamoxifen concentration data were included in the analysis. CYP2D6 was the primary gene associated with the tamoxifen metabolism pathway, especially the conversion of tamoxifen to endoxifen. CYP3A4 and CYP2C9 were also responsible for the metabolism of tamoxifen. CYP2C9 especially impacted the hydroxylation to 4-OHtam, and this involved the OATP1B1 (SLCO1B1) transporter. Conclusion: Multiple genes are involved in tamoxifen metabolism and multi-gene panels could be useful to predict active metabolite concentrations and guide tamoxifen dosing.

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Effect of OATP1B1 genetic polymorphism on the uptake of tamoxifen and its metabolite, endoxifen

Cited by 16 publications

References 23 publications

Identification of anticancer OATP2B1 substrates by an in vitro triple-fluorescence-based cytotoxicity screen

Identification of anticancer OATP2B1 substrates by an in vitro triple-fluorescence-based cytotoxicity screen

CYP2C9 and OATP1B1 genetic polymorphisms affect the metabolism and transport of glimepiride and gliclazide

Effect of Genetic Variability in 20 Pharmacogenes on Concentrations of Tamoxifen and Its Metabolites

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