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Related Experiment Video

Updated: May 2, 2026

Generation of a Rat Model of Acute Liver Failure by Combining 70% Partial Hepatectomy and Acetaminophen

Generation of a Rat Model of Acute Liver Failure by Combining 70% Partial Hepatectomy and Acetaminophen

Published on: November 27, 2019

TRPM2 channels mediate acetaminophen-induced liver damage.

Ehsan Kheradpezhouh¹, Linlin Ma, Arthur Morphett

¹Discipline of Physiology, School of Medical Sciences, University of Adelaide, Adelaide, SA 5005, Australia.

Proceedings of the National Academy of Sciences of the United States of America

|February 27, 2014

Summary

Acetaminophen overdose causes liver damage by increasing intracellular calcium via the TRPM2 channel. Blocking this channel significantly reduces acetaminophen-induced liver injury in mice.

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Area of Science:

Hepatology
Molecular Biology
Pharmacology

Background:

Acetaminophen (paracetamol) overdose is a leading cause of acute liver failure and chronic liver damage.
Acetaminophen overdose triggers complex biochemical reactions in liver cells (hepatocytes), including calcium imbalance.
The specific source of increased intracellular calcium during acetaminophen overdose has remained unclear.

Purpose of the Study:

To identify the calcium channel responsible for calcium influx in hepatocytes during acetaminophen overdose.
To investigate the role of this calcium channel in acetaminophen-induced liver toxicity.

Main Methods:

Whole-cell patch-clamp electrophysiology to measure cation currents in hepatocytes.
siRNA-mediated knockdown of TRPM2 in hepatocytes.
Assessment of acetaminophen-induced liver damage in TRPM2 knockout mice versus wild-type mice using liver enzyme levels and histology.

Main Results:

Acetaminophen treatment activated a cation current in hepatocytes, similar to currents activated by hydrogen peroxide (H2O2) or ADP-ribose.
siRNA knockdown of the Transient Receptor Potential Melanostatine 2 (TRPM2) channel inhibited this current activation by acetaminophen and H2O2.
TRPM2 knockout mice exhibited significantly reduced liver damage following acetaminophen overdose compared to wild-type mice.

Conclusions:

The Transient Receptor Potential Melanostatine 2 (TRPM2) cation channel is essential for calcium entry into hepatocytes during acetaminophen overdose.
TRPM2 channels play a critical role in the mechanism of acetaminophen-induced hepatocellular death.
Targeting TRPM2 channels may offer a therapeutic strategy for acetaminophen overdose.