Background: During clinical trials bosentan, the first orally active endothelin receptor antagonist, caused asymptomatic transaminase elevations in some patients. In this study we investigated whether inhibition of the hepatocanalicular bile salt export pump (rodents, Bsep; humans, BSEP ABCB11) could account for bosentan-induced liver injury.
Methods: We reanalyzed the safety database of the bosentan trials for cholestatic liver injury, determined the cholestatic potency of bosentan in the rat, and studied the effects of bosentan and its metabolites on Bsep-mediated taurocholate transport in vitro.
Results: Bosentan caused dose-dependent and reversible liver injury in 2% to 18% of patients and caused a significant increase of serum bile salt levels (P <.01). Concomitant administration of glyburide (INN, glibenclamide) enhanced the cholestatic potency of bosentan. Similar effects were seen in rats, in which serum bile salt levels were increased by glyburide less than by bosentan, which increased the levels less than a combination of bosentan and glyburide. In vitro, Bsep-mediated taurocholate transport was inhibited by bosentan (inhibition constant, approximately 12 micromol/L) and metabolites (inhibition constant, approximately 8.5 micromol/L for metabolite Ro 47-8634).
Conclusions: These results indicate that bosentan-induced liver injury is mediated, at least in part, by inhibition of Bsep/BSEP-causing intracellular accumulation of cytotoxic bile salts and bile salt induced liver cell damage. The data further emphasize the pathophysiologic importance of drug-Bsep interactions in acquired forms of cholestatic liver injury.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1067/mcp.2001.114667 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Introduction: The intestinal dysfunction plays an important role in the decreased growth performance of broiler chickens under high stocking density. Gut microbiota plays an important role in maintaining intestinal health. However, the modulation pathway of gut microbiota by regulating the intestinal barrier and histomorphology remains unknown.
View Article and Find Full Text PDFMitochondria-targeted nanovesicles for ursodeoxycholic acid delivery to combat neurodegeneration by ameliorating mitochondrial dysfunction.
J Nanobiotechnology
March 2025
Institute of Translational Medicine, Shanghai University, Shanghai, 200444, China.
Mitochondria are pivotal in sustaining oxidative balance and metabolic activity within neurons. It is well-established that mitochondrial dysfunction constitutes a fundamental pathogenic mechanism in neurodegeneration, especially in the context of Parkinson's disease (PD), this represents a promising target for therapeutic intervention. Ursodeoxycholic acid (UDCA), a clinical drug used for liver disease, possesses antioxidant and mitochondrial repair properties.
View Article and Find Full Text PDFMolecular Classification of Hepatocellular Carcinoma based on Zoned Metabolic Feature and Oncogenic Signaling Pathway.
Clin Mol Hepatol
March 2025
Department of Gastroenterology and Hepatology/Kindai University Faculty of Medicine, Osaka-Sayama, Japan.
Background/aims: Previously, we advocated the importance of classifying hepatocellular carcinoma (HCC) based on physiological functions. This study aims to classify HCC by focusing on liver-intrinsic metabolism and glycolytic pathway in cancer cells.
Methods: Comprehensive RNA/DNA sequencing, immunohistochemistry, and radiological evaluations were performed on HCC tissues from the training cohort (n=136) and validated in 916 public samples.
Predicting Liver-Related In Vitro Endpoints with Machine Learning to Support Early Detection of Drug-Induced Liver Injury.
Chem Res Toxicol
March 2025
Bayer AG, Pharmaceuticals, 13353 Berlin, Germany.
Drug-induced liver injury (DILI) is a major cause of drug development failures and postmarket drug withdrawals, posing significant challenges to public health and pharmaceutical research. The biological mechanisms leading to DILI are highly complex and the adverse reaction is often difficult to foresee. Hence, mechanistic insights into DILI, as well as machine learning models to predict molecular events that trigger adverse outcomes, pharmacokinetics and pharmacodynamics in the liver, are essential tools for understanding and preventing DILI.
View Article and Find Full Text PDFEfficacy and mechanism of inhibition of the GPR30-PI3K pathway by 4-phenylbutyric acid in the treatment of intrahepatic cholestasis of pregnancy.
J Mol Histol
March 2025
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, No. 1 of Youyi Road, Yuanjiagang, Daping Street, Yuzhong District, Chongqing, 400042, China.
Intrahepatic cholestasis of pregnancy (ICP) is a liver disease that manifests predominantly in the later stages of pregnancy. The primary treatment currently involves the use of ursodeoxycholic acid (UDCA). In this study, the therapeutic effectiveness of 4-phenylbutyric acid (4-PBA) in the treatment of ICP, as well as the potential mechanisms involved, are investigated to offer new references for clinical treatment decisions using ICP model.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!