Related Experiment Video

Updated: Apr 15, 2026

Human Liver Microphysiological System for Assessing Drug-Induced Liver Toxicity In Vitro
11:06

Human Liver Microphysiological System for Assessing Drug-Induced Liver Toxicity In Vitro

Published on: January 31, 2022

5.6K

Mechanisms of tolvaptan-induced toxicity in HepG2 cells

Yuanfeng Wu1, Frederick A Beland1, Si Chen1

  • 1Division of Biochemical Toxicology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR 72079, USA.

Biochemical Pharmacology
|April 11, 2015
PubMed

Insights

Tolvaptan, a drug for hyponatremia, can cause liver injury. This study shows tolvaptan induces cell death by damaging DNA, disrupting cell cycle, and triggering apoptosis in liver cells.

Area of Science:

  • Hepatotoxicity and molecular toxicology.
  • Cellular and molecular mechanisms of drug-induced liver injury.

Background:

  • Tolvaptan is a vasopressin V2 receptor antagonist used to treat hyponatremia.
  • Recent reports link tolvaptan use to an increased risk of liver injury.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying tolvaptan-induced hepatotoxicity.
  • To elucidate the cellular pathways affected by tolvaptan in liver cells.

Main Methods:

  • Utilized human HepG2 cells to study tolvaptan effects.
  • Assessed cell viability, cell cycle progression, DNA damage (comet assay, 8-oxoguanine, H2AX phosphorylation), apoptosis (cytochrome C release, Bcl-2 family modulation, p38 activation), proteasome activity, and autophagy.

Main Results:

  • Tolvaptan inhibited HepG2 cell growth and induced cell death in a dose- and time-dependent manner.
  • Observed delayed cell cycle progression, DNA damage, apoptosis induction, and activation of p38 signaling.
  • Tolvaptan treatment modulated proteasome activity and induced autophagy, impacting cytotoxicity.

Conclusions:

  • Tolvaptan cytotoxicity stems from cell cycle arrest, DNA damage, and apoptosis induction.
  • Perturbation of multiple signaling pathways, including p38, proteasome, and autophagy, contributes to tolvaptan's toxic effects on liver cells.
Keywords:
ApoptosisAutophagyDNA damageLiver injuryProteasomeTolvaptan

More Related Videos

Inducing and Characterizing Vesicular Steatosis in Differentiated HepaRG Cells09:15

Inducing and Characterizing Vesicular Steatosis in Differentiated HepaRG Cells

Published on: July 18, 2019

9.7K
Drug-Induced Senescence in Liver Cells Promotes M2 Macrophage Polarization: Implications for Tyrosine Kinase Inhibitor-Associated Hepatotoxicity09:32

Drug-Induced Senescence in Liver Cells Promotes M2 Macrophage Polarization: Implications for Tyrosine Kinase Inhibitor-Associated Hepatotoxicity

Published on: October 17, 2025

650

Related Concept Videos

Drug Toxicity: Dose-Dependent Reactions01:24

Drug Toxicity: Dose-Dependent Reactions

Drug toxicities can be stratified into pharmacological, pathological, or genotoxic based on their mechanisms. The incidence and severity of these toxicities generally increase with the drug's concentration in the body and exposure time.Pharmacological toxicity is evident when the therapeutic effects of drugs overshoot into adverse reactions in a predictable, dose-dependent manner. Central nervous system (CNS) depression from barbiturates is a classic example, with effects escalating from...
209
Drug toxicity: Idiosyncratic Reactions01:16

Drug toxicity: Idiosyncratic Reactions

Idiosyncratic drug reactions represent abnormal chemical responses that vary significantly among individuals, ranging from extreme sensitivity to low doses to insensitivity to high doses. These reactions often occur due to the drug's covalent binding with serum proteins, forming a foreign hapten that triggers an immunotoxicological response. The variability in drug reactions has a strong pharmacogenetic foundation, with genetic differences crucial in how individuals metabolize drugs. For...
197
Drug Toxicity: Allergic Reactions01:30

Drug Toxicity: Allergic Reactions

Drug-related allergies are immune-mediated responses triggered by the administration of pharmacological agents. These hypersensitivity reactions are classified based on the immune mechanisms involved. The four primary types—Type I, II, III, and IV—are mediated by different immunological pathways and exhibit distinct clinical manifestations.Type I Hypersensitivity/ IgE-Mediated Reactions: Immunoglobulin E (IgE) immediately mediates Type I hypersensitivity reactions. Upon initial...
173
Pharmacogenetics of Phase II Enzymes: N-acetyltransferase, Thiopurine S-methyltransferase, UDP-glucuronosyltransferase01:27

Pharmacogenetics of Phase II Enzymes: N-acetyltransferase, Thiopurine S-methyltransferase, UDP-glucuronosyltransferase

Phase II biotransformation reactions are essential for detoxifying and eliminating xenobiotics, including many pharmaceutical compounds. These reactions typically involve conjugation, the covalent attachment of polar endogenous groups such as glucuronic acid, sulfate, methyl, or acetyl moieties to functional groups introduced during Phase I metabolism. The resulting conjugates are more water-soluble, enabling efficient renal or biliary excretion.The major classes of Phase II enzymes include...
78
Drug toxicity: Drug–Drug Interaction01:30

Drug toxicity: Drug–Drug Interaction

Drug–drug interactions can precipitate toxicity through multiple mechanisms. Absorption interactions alter how drugs enter the body, exemplified when ranitidine increases the absorption of basic drugs, while cholestyramine decreases the levels of propranolol. Protein binding interactions occur when drugs share the same binding sites on plasma proteins. Drugs like aspirin and warfarin, when bound in excess, can lead to increased free drug concentrations, enhancing the potential for...
376
Bioactivation and Tissue Toxicity01:25

Bioactivation and Tissue Toxicity

Bioactivation is a metabolic process that transforms less reactive substances into highly reactive metabolites, initiating tissue toxicity. This transformation can lead to various toxic effects, including carcinogenesis and teratogenesis. Reactive metabolites are classified into two main types: electrophiles and free radicals.Electrophiles are electron-deficient species and are produced primarily by the enzyme cytochrome P-450 during the metabolism of compounds containing carbon, nitrogen, or...
134