Evidence map›Paper›PMID 31907698›Full record

ArticlePharmaceutical research2020

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

Brandy Garzel, Tao Hu, Linhao Li, Yuanfu Lu, Scott Heyward, James Polli, Lei Zhang, Shiew-Mei Huang, Jean-Pierre Raufman, Hongbing Wang

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Pharmaceutical research, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.

0numbers the graph read from it
0cells of the map it votes in
8citing papers in PubMed
1.3field-weighted citation impact, top 17% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

8 citing papers in PubMed, 21 citations in OpenAlex.

  1. Trial
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

10 authors at 3 institutions in 2 countries.

Brandy GarzelDepartment of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, Maryland, 21201, USA.
Tao HuDepartment of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, Maryland, 21201, USA.
Linhao LiDepartment of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, Maryland, 21201, USA.
Yuanfu LuKey Laboratory of Pharmacology of Ministry of Education, Zunyi Medical University, Zunyi, China.
Scott HeywardBioIVT, 1450 S Rolling Road, Baltimore, Maryland, 21227, USA.
James PolliDepartment of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, Maryland, 21201, USA.
Lei ZhangOffice of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, 20993, USA.
Shiew-Mei HuangOffice of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, 20993, USA.
Jean-Pierre RaufmanDivision of Gastroenterology and Hepatology, University of Maryland School of Medicine, 22 South Greene Street, Baltimore, Maryland, 21201, USA.
Hongbing WangDepartment of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, Maryland, 21201, USA. hongbing.wang@rx.umaryland.edu.ORCID http://orcid.org/0000-0002-6224-6888
University of Maryland, Baltimore · USCenter for Drug Evaluation and Research · USZunyi Medical University · CN

Funding

University of Maryland Center of Excellence in Regulatory Science and InnovationU01FD005946 · FDA · UNIV OF MARYLAND, COLLEGE PARK · PI BENTLEY, WILLIAM E., POLLI, JAMES E · 2016 to 2025
$21.5M
Function and Regulation of SLC13A5 in the LiverR01GM121550 · NIGMS · UNIVERSITY OF MARYLAND BALTIMORE · PI WANG, HONGBING · 2018 to 2021
$1.3M
Role of BSEP in Drug-Induced Cholestatic Liver ToxicityF31DK105750 · NIDDK · UNIVERSITY OF MARYLAND BALTIMORE · PI GARZEL, BRANDY · 2015 to 2016
$57k
M3R, MMP1 and Colon Cancer DisseminationI01BX002129 · VA · BALTIMORE VA MEDICAL CENTER · PI RAUFMAN, JEAN-PIERRE · 2015 to 2018
–
BLRD VA I01 BX002129FDA HHS U01 FD005946NIDDK NIH HHS F31 DK105750NIGMS NIH HHS GM121550NIGMS NIH HHS R01 GM121550U.S. Department of Veterans Affairs BX002129U.S. Food and Drug Administration ORISE Fellow
6 · The paper itself

Abstract

purposeThe 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.

methodsBSEP 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.

resultsMetformin 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.

conclusionsRepression 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.

Indexed as

ATP Binding Cassette Transporter, Subfamily B, Member 11BileBile Acids and SaltsBiological TransportCell LineCholestasisHepatocytesHumansLiverMetforminATP Binding Cassette Transporter, Subfamily B, Member 11Bile Acids and SaltsMetforminBSEPCholestasisGene regulationMetforminTamoxifen

Identifiers

PMID31907698
PMCPMC7357855
OpenAlexW2996776347

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.