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Characterization of Plasma Membrane Localization and Phosphorylation Status of Organic Anion Transporting Polypeptide (OATP) 1B1 c.521 T>C Nonsynonymous Single-Nucleotide Polymorphism

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Abstract

Purpose

Membrane transport protein organic anion transporting polypeptide (OATP) 1B1 mediates hepatic uptake of many drugs (e.g. statins). The OATP1B1 c.521 T > C (p. V174A) polymorphism has reduced transport activity. Conflicting in vitro results exist regarding whether V174A-OATP1B1 has reduced plasma membrane localization; no such data has been reported in physiologically relevant human liver tissue. Other potential changes, such as phosphorylation, of the V174A-OATP1B1 protein have not been explored. Current studies characterized the plasma membrane localization of V174A-OATP1B1 in genotyped human liver tissue and cell culture and compared the phosphorylation status of V174A- and wild-type (WT)-OATP1B1.

Methods

Localization of V174A- and WT-OATP1B1 were determined in OATP1B1 c.521 T > C genotyped human liver tissue (n = 79) by immunohistochemistry and in transporter-overexpressing human embryonic kidney (HEK) 293 and HeLa cells by surface biotinylation and confocal microscopy. Phosphorylation and transport of OATP1B1 was determined using 32P-orthophosphate labeling and [3H]estradiol-17β-glucuronide accumulation, respectively.

Results

All three methods demonstrated predominant plasma membrane localization of both V174A- and WT-OATP1B1 in human liver tissue and in cell culture. Compared to WT-OATP1B1, the V174A-OATP1B1 has significantly increased phosphorylation and reduced transport.

Conclusions

We report novel findings of increased phosphorylation, but not impaired membrane localization, in association with the reduced transport function of the V174A-OATP1B1.

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Abbreviations

DDI:

Drug-drug interaction

DMEM:

Dulbecco’s modified Eagle medium

DPBS:

Dulbecco’s phosphate-buffered saline

E217βG:

Estradiol 17β-glucuronide

HBSS:

Hanks balanced salt solution

HEK:

Human embryonic kidney

OATP:

Organic anion transporting polypeptide

SLCO:

Solute carrier organic anion

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Acknowledgments and Disclosures

We would like to thank Dr. Dietrich Keppler for providing the HEK293-Mock stable cell line and Dr. Allison Gillaspy for designing the PCR primers.

This research was supported by NIH R01 GM094268 [W. Y]. The Olympus FV10i confocal microscope is supported by equipment grants from the NIH to Dr. Wei Yue (R01GM094268-06S1) and from the Presbyterian Health Foundation to Dr. Kelly Standifer. Research reported in this publication was supported in part by the National Cancer Institute Cancer Center Support Grant P30CA225520 awarded to the University of Oklahoma Stephenson Cancer Center and the Molecular Biology Shared Resource. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Alexandra Crowe is an American Foundation of Pharmaceutical Education pre-doctoral Fellow.

Reprint requests should be addressed to Wei Yue, 1110 N. Stonewall Avenue, Oklahoma City, OK 73117. E-mail: wei-yue@ouhsc.edu

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, 1110 N. Stonewall Avenue, Oklahoma City, OK, 73117, USA

    Alexandra Crowe, Jonathan Miller, Sonia Pahwa, Khondoker Alam & Wei Yue

  2. Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Wei Zheng, Kar-Ming Fung, Erin Rubin & Feng Yin

  3. Department of Biostatistics and Epidemiology, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Kai Ding

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  1. Alexandra Crowe
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Contributions

Participated in research design: Yue, Crowe, Zheng, Fung.

Conducted experiments: Crowe, Miller, Pahwa, Alam, Yue.

Contributed new reagents or analytic tools: Zheng, Fung, Rubin, Yin.

Performed data analysis: Zheng, Fung, Rubin, Ding, Yue.

Wrote or contributed to writing the manuscript: Crowe, Yue.

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Correspondence to Wei Yue.

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Crowe, A., Zheng, W., Miller, J. et al. Characterization of Plasma Membrane Localization and Phosphorylation Status of Organic Anion Transporting Polypeptide (OATP) 1B1 c.521 T>C Nonsynonymous Single-Nucleotide Polymorphism. Pharm Res 36, 101 (2019). https://doi.org/10.1007/s11095-019-2634-3

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