Related Experiment Video
Updated: Dec 31, 2025
08:42
Using Multi-fluorinated Bile Acids and In Vivo Magnetic Resonance Imaging to Measure Bile Acid Transport
Published on: November 27, 2016
11.5K
Metformin Disrupts Bile Acid Efflux by Repressing Bile Salt Export Pump Expression
Brandy Garzel1, Tao Hu1, Linhao Li1
1Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, Maryland, 21201, USA.
Pharmaceutical Research
|January 8, 2020
Summary
Drug-induced cholestasis can occur through bile salt export pump (BSEP) repression. Metformin and tamoxifen reduce BSEP expression, disrupting bile acid efflux and potentially causing liver injury.
Area of Science:
- Hepatology
- Pharmacology
- Toxicology
Background:
- The bile salt export pump (BSEP) is crucial for clearing bile acids from the liver.
- Drug-induced cholestasis research often focuses on direct BSEP inhibition.
- Transcriptional repression of BSEP is an understudied mechanism for cholestasis.
Purpose of the Study:
- To investigate the disruption of bile acid efflux caused by drug-induced BSEP repression.
- To explore whether BSEP repression can lead to cholestasis.
- To identify drugs that may cause cholestasis via BSEP repression.
Main Methods:
- Analyzed BSEP activity in human primary hepatocytes (HPH).
- Utilized traditional biliary-clearance and modified efflux assays with 72-h pretreatment.
- Examined BSEP mRNA and protein expression via RT-PCR and Western blotting.
Main Results:
- Metformin concentration-dependently repressed BSEP expression in HPH.
- Metformin exposure reduced BSEP transport function by down-regulating BSEP expression, independent of AMP-activated protein kinase.
- Tamoxifen also repressed BSEP expression and reduced BSEP activity in HPH.
Conclusions:
- BSEP repression alone is sufficient to disrupt hepatic bile acid efflux.
- Metformin and tamoxifen are identified as BSEP repressors.
- These drugs may cause drug-induced cholestasis through gene repression rather than direct BSEP inhibition.
Related Concept Videos
01:16Hepatic Drug Excretion: Influencing Factors
481
The biliary system of the liver, crucial for bile secretion and drug excretion, comprises intrahepatic bile ducts that merge to form the common hepatic duct. This duct, carrying hepatic bile, combines with the cystic duct, draining the gallbladder and forming the common bile duct, which empties into the duodenum. Bile, produced by hepatic cells lining the bile canaliculi, is composed primarily of water, bile salts, pigments, electrolytes, and lesser amounts of cholesterol and fatty acids. Bile...
481
01:17Hepatic Drug Excretion: Enterohepatic Cycling
2.4K
Enterohepatic cycling involves the active secretion of drugs and their metabolites into the bile via transporters in the canalicular membrane of hepatocytes. This secretion is an integral part of the digestive process, releasing these substances into the gastrointestinal (GI) tract.
Post-release drugs and metabolites can be reabsorbed into the body from the intestine. For conjugated metabolites like glucuronides, reabsorption requires enzymatic hydrolysis by intestinal microflora. This...
Post-release drugs and metabolites can be reabsorbed into the body from the intestine. For conjugated metabolites like glucuronides, reabsorption requires enzymatic hydrolysis by intestinal microflora. This...
2.4K
01:14Hepatic Drug Clearance: Role of Transporters
266
In the liver and bile canaliculi, influx and efflux transporters modification can influence intrinsic clearance. Transporters play a significant role in moving drugs within liver cells. Elaborate models, such as the Biopharmaceutical Classification System (BCS), are essential to relate transporters to drug disposition. This system categorizes drugs into four classes based on solubility and permeability, providing insights into elimination routes and the effects of transporters following oral...
266
01:26Oral Hypoglycemic Agents: Biguanides and Glitazones
539
Biguanides, particularly metformin (Glucophage), are insulin sensitizers that enhance glucose uptake, thereby reducing insulin resistance. Unlike sulfonylureas, metformin doesn't prompt insulin secretion, which helps to curb hypoglycemia risk. Metformin is beneficial in treating conditions like polycystic ovary syndrome due to its insulin-resistance reduction capability. The drug's primary action involves curtailing hepatic gluconeogenesis, a significant contributor to high blood...
539
01:20Pharmacokinetics in Obese Patients: Drug Metabolism and Excretion
133
Drug metabolism, a critical process in the liver, involves two primary phases: Phase I reactions and Phase II conjugation. Obesity introduces significant alterations in this metabolic process, primarily due to fatty infiltration of the liver, leading to conditions such as nonalcoholic fatty liver disease (NAFLD). This condition can modify the activities of both Phase I and II enzymes, impacting how drugs are metabolized in obese patients.Phase I metabolism sees variable effects across...
133
01:25Pharmacokinetics in Obese Patients: Drug Absorption and Distribution
193
Obesity significantly alters the pharmacokinetic processes of drug absorption and distribution, presenting unique challenges in medical treatment. The increased fat tissue and decreased lean muscle in obese individuals can significantly affect how drugs are absorbed into the body and distributed across different tissues. This alteration can lead to variances in the effectiveness and safety of medications, necessitating adjustments in dosing or drug selection for obese patients.One notable...
193