TRPM2 channels mediate acetaminophen-induced liver damage

Kheradpezhouh, Ehsan, Ma, Linlin, Morphett, Arthur, Barritt, Greg J. and Rychkov, Grigori Y. (2014) TRPM2 channels mediate acetaminophen-induced liver damage. Proceedings of the National Academy of Sciences of the United States of America (PNAS), 111 8: 3176-3181. doi:10.1073/pnas.1322657111


Author Kheradpezhouh, Ehsan
Ma, Linlin
Morphett, Arthur
Barritt, Greg J.
Rychkov, Grigori Y.
Title TRPM2 channels mediate acetaminophen-induced liver damage
Journal name Proceedings of the National Academy of Sciences of the United States of America (PNAS)   Check publisher's open access policy
ISSN 0027-8424
1091-6490
Publication date 2014-02-25
Year available 2014
Sub-type Article (original research)
DOI 10.1073/pnas.1322657111
Open Access Status Not Open Access
Volume 111
Issue 8
Start page 3176
End page 3181
Total pages 6
Place of publication Washington, DC, United States
Publisher National Academy of Sciences
Language eng
Formatted abstract
Acetaminophen (paracetamol) is the most frequently used analgesic and antipyretic drug available over the counter. At the same time, acetaminophen overdose is the most common cause of acute liver failure and the leading cause of chronic liver damage requiring liver transplantation in developed countries. Acetaminophen overdose causes a multitude of interrelated biochemical reactions in hepatocytes including the formation of reactive oxygen species, deregulation of Ca2+ homeostasis, covalent modification and oxidation of proteins, lipid peroxidation, and DNA fragmentation. Although an increase in intracellular Ca2+ concentration in hepatocytes is a known consequence of acetaminophen overdose, its importance in acetaminophen-induced liver toxicity is not well understood, primarily due to lack of knowledge about the source of the Ca2+ rise. Here we report that the channel responsible for Ca2+ entry in hepatocytes in acetaminophen overdose is the Transient Receptor Potential Melanostatine 2 (TRPM2) cation channel. We show by whole-cell patch clamping that treatment of hepatocytes with acetaminophen results in activation of a cation current similar to that activated by H2O2 or the intracellular application of ADP ribose. siRNA-mediated knockdown of TRPM2 in hepatocytes inhibits activation of the current by either acetaminophen or H2O2. In TRPM2 knockout mice, acetaminophen-induced liver damage, assessed by the blood concentration of liver enzymes and liver histology, is significantly diminished compared with wild-type mice. The presented data strongly suggest that TRPM2 channels are essential in the mechanism of acetaminophen-induced hepatocellular death.
Keyword TRPM2 channels
Liver damage
Acetaminophen
Paracetamol
Ca2+
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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Created: Wed, 04 May 2016, 21:05:11 EST by Linlin Ma on behalf of School of Chemistry & Molecular Biosciences