ArticleThe Journal of pharmacology and experimental therapeutics2022
Novel Bile Acid-Dependent Mechanisms of Hepatotoxicity Associated with Tyrosine Kinase Inhibitors.
Article in The Journal of pharmacology and experimental therapeutics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 30 citations in OpenAlex.
- Advances in the design and discovery of small-molecule tyrosine kinase inhibitors for breast cancer.RSC advances · 2026Review
- A Case of Acalculous Cholecystitis During Lenvatinib Plus Pembrolizumab Therapy for Advanced Renal Cell Carcinoma.IJU case reports · 2026Article
- A case of recurrent acute acalculous cholecystitis in a patient with renal cell carcinoma treated with pazopanib and axitinib: case report and literature review.Frontiers in pharmacology · 2026Article
- From mechanisms to practice: risk management and multidisciplinary decision-making for systemic treatment-related liver injury in HBV-associated hepatocellular carcinoma.Frontiers in pharmacology · 2026Review
- Prevalence of gastrointestinal side effects in hepatocellular carcinoma patients receiving sorafenib: a meta-analysis of 136 studies and 14,416 patients.Therapeutic advances in medical oncology · 2026Article
- Evaluation of a human 3D multicellular hepatic spheroid model as a platform for studying hepatic transporters.Cellular and molecular life sciences : CMLS · 2025Article
- Immune-related hepatic adverse events in renal cell carcinoma patients treated with immune checkpoint inhibitors: a retrospective study.BJC reports · 2025Article
- Amino Acid Hepatotoxicity Biomarkers in Human Hepatic Organoids: Promising Standardization of Drug Toxicity Evaluation.ACS pharmacology & translational science · 2025Article
- Development of anFrontiers in pharmacology · 2025Article
- Hepatotoxicity associated with anti-neoplastic agents: a pharmacovigilance analysis of the Food and Drug Administration Adverse Event Reporting System database.Frontiers in immunology · 2025Article
- Kinase Inhibitors FDA Approved 2018-2023: Drug Targets, Metabolic Pathways, and Drug-Induced Toxicities.Drug metabolism and disposition: the biological fate of chemicals · 2024Review
- Real-world data on the management of pazopanib-induced liver toxicity in routine care of renal cell cancer and soft tissue sarcoma patients.Cancer chemotherapy and pharmacology · 2024Observational
- Hepatic Bile Acid Transporters and Drug-induced Hepatotoxicity.Toxicologic pathology · 2023Review
- Advances in Idiosyncratic Drug-Induced Liver Injury Issues: New Clinical and Mechanistic Analysis Due to Roussel Uclaf Causality Assessment Method Use.International journal of molecular sciences · 2023Review
- The role of cytochrome P450 3A4-mediated metabolism in sorafenib and lapatinib hepatotoxicity.Livers · 2023Article
- Adverse reactions after treatment with dasatinib in chronic myeloid leukemia: Characteristics, potential mechanisms, and clinical management strategies.Frontiers in oncology · 2023Review
- Effect of mTOR inhibitors on sodium taurocholate cotransporting polypeptide (NTCP) functionFrontiers in pharmacology · 2023Article
- A novel differentiated HuH-7 cell model to examine bile acid metabolism, transport and cholestatic hepatotoxicity.Scientific reports · 2022Article
- Risk Factors for Hepatic Encephalopathy in Hepatocellular Carcinoma After Sorafenib or Lenvatinib Treatment: A Real-World Study.Drug design, development and therapy · 2022Article
- Pharmacotherapies for Drug-Induced Liver Injury: A Current Literature Review.Frontiers in pharmacology · 2021Review
Corrections and comments
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Authors and funding
6 authors at 1 institution in 3 countries.
Funding
Abstract
Drug-induced liver injury (DILI) is the leading cause of acute liver failure and a major concern in drug development. Altered bile acid homeostasis via inhibition of the bile salt export pump (BSEP) is one mechanism of DILI. Dasatinib, pazopanib, and sorafenib are tyrosine kinase inhibitors (TKIs) that competitively inhibit BSEP and increase serum biomarkers for hepatotoxicity in ∼25-50% of patients. However, the mechanism(s) of hepatotoxicity beyond competitive inhibition of BSEP are poorly understood. This study examined mechanisms of TKI-mediated hepatotoxicity associated with altered bile acid homeostasis. Dasatinib, pazopanib, and sorafenib showed bile acid-dependent toxicity at clinically relevant concentrations, based on the C-DILI assay using sandwich-cultured human hepatocytes (SCHH). Among several bile acid-relevant genes, cytochrome P450 (CYP) 7A1 mRNA was specifically upregulated by 6.2- to 7.8-fold (dasatinib) and 5.7- to 9.3-fold (pazopanib), compared with control, within 8 hours. This was consistent with increased total bile acid concentrations in culture medium up to 2.3-fold, and in SCHH up to 1.4-fold, compared with control, within 24 hours. Additionally, protein abundance of sodium taurocholate co-transporting polypeptide (NTCP) was increased up to 2.0-fold by these three TKIs. The increase in NTCP protein abundance correlated with increased function; dasatinib and pazopanib increased hepatocyte uptake clearance (CL
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Registered trials
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.