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Metformin Disrupts Bile Acid Efflux by Repressing Bile Salt Export Pump Expression

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Abstract

Purpose

The bile salt export pump (BSEP), a key player in hepatic bile acid clearance, has been the center of research on drug-induced cholestasis. However, such studies focus primarily on the direct inhibition of BSEP, often overlooking the potential impact of transcriptional repression. This work aims to explore the disruption of bile acid efflux caused by drug-induced BSEP repression.

Methods

BSEP activity was analyzed in human primary hepatocytes (HPH) using a traditional biliary-clearance experiment and a modified efflux assay, which includes a 72-h pretreatment prior to efflux measurement. Relative mRNA and protein expressions were examined by RT-PCR and Western blotting, respectively.

Results

Metformin concentration-dependently repressed BSEP expression in HPH. Although metformin did not directly inhibit BSEP activity, longer metformin exposure reduced BSEP transport function in HPH by down-regulating BSEP expression. BSEP repression by metformin was found to be AMP-activated protein kinase-independent. Additional screening of 10 reported cholestatic non-BSEP inhibitors revealed that the anti-cancer drug tamoxifen also markedly repressed BSEP expression and reduced BSEP activity in HPH.

Conclusions

Repression of BSEP alone is sufficient to disrupt hepatic bile acid efflux. Metformin and tamoxifen appear to be prototypes of a class of BSEP repressors that may cause drug-induced cholestasis through gene repression instead of direct BSEP inhibition.

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Abbreviations

AMPK :

AMP-activated protein kinase

BEI :

Biliary excretion index.

BSEP :

Bile salt export pump.

DILI :

Drug-induced liver injury.

DIC :

Drug-induced cholestasis.

HPH :

Human primary hepatocytes.

MRP :

Multidrug resistance-associated protein.

OST :

Organic solute transporter.

P-gp :

P-glycoprotein.

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Author information

Author notes

  1. Brandy Garzel and Tao Hu contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, Maryland, 21201, USA

    Brandy Garzel, Tao Hu, Linhao Li, James Polli & Hongbing Wang

  2. Key Laboratory of Pharmacology of Ministry of Education, Zunyi Medical University, Zunyi, China

    Yuanfu Lu

  3. BioIVT, 1450 S Rolling Road, Baltimore, Maryland, 21227, USA

    Scott Heyward

  4. Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, 20993, USA

    Lei Zhang & Shiew-Mei Huang

  5. Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, 22 South Greene Street, Baltimore, Maryland, 21201, USA

    Jean-Pierre Raufman

  6. VA Maryland Health Care System, 10 N. Greene Street, Baltimore, Maryland, 21201, USA

    Jean-Pierre Raufman

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  1. Brandy Garzel
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Garzel, B., Hu, T., Li, L. et al. Metformin Disrupts Bile Acid Efflux by Repressing Bile Salt Export Pump Expression. Pharm Res 37, 26 (2020). https://doi.org/10.1007/s11095-019-2753-x

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  • DOI: https://doi.org/10.1007/s11095-019-2753-x

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