Oral Presentation 2014 International Biophysics Congress

TRPM2 channels as mediators of paracetamol-induced liver damage (#98)

Grigori Rychkov 1 2
  1. South Australian Health and Medical Research Institute, Adelaide, SA, Australia
  2. School of Medicine, University of Adelaide, Adelaide, SA, Australia

Transient Receptor Potential Melastatine 2 (TRPM2) protein is a non-selective cation channel and a member of the TRP channels family1 . It is expressed in most tissues, including liver, and is found in both plasma membrane and lysosomes. TRPM2 has unique gating properties, being activated by several stimuli including ADP-ribose (ADPR), nicotinamide adenine dinucleotide (NAD) and H2O2. Intracellular Ca2+ plays a role of an important co-factor in channel activation, increasing TRPM2 sensitivity to ADPR (for review, see 2 ). Gating of TRPM2 by H2O2, other reactive oxygen species and ADPR may have significant implications in pathophysiological processes. Our recent research suggests that TRPM2 channels are essential in the mechanism of paracetamol-induced liver damage3 . Paracetamol is the most commonly used analgesic and antipyretic drug. At the same time, paracetamol overdose is the most common cause of acute liver failure and the leading cause of liver failure requiring liver transplantation in developed countries. In hepatocytes, paracetamol overdose causes formation of ROS, deregulation of Ca2+ homeostasis, covalent modification and oxidation of proteins, lipid peroxidation, and DNA fragmentation. Using whole cell patch clamping, Ca2+ imaging and confocal microscopy we show that treatment of hepatocytes with paracetamol results in activation of Ca2+ entry and a cation current similar to that activated by H2O2 or the intracellular application of ADP-ribose. Furthermore, paracetamol-induced liver damage in TRPM2 knock-out mice, assessed by liver histology and the concentration of liver enzymes in the blood is significantly attenuated compared to wild-type mice. Presented results suggest that elevation in cytoplasmic Ca2+ induced in human liver by paracetamol overdose is mediated by TRPM2 channels and that blockade of TRPM2 may prove useful in treatment of paracetamol overdose and other liver diseases associated with oxidative damage. 

  1. Nagamine, K., et al., Molecular Cloning of a Novel Putative Ca2+Channel Protein (TRPC7) Highly Expressed in Brain. Genomics, 1998. 54:124-131.
  2. Perraud, A.L., C. Schmitz, and A.M. Scharenberg, TRPM2 Ca2+ permeable cation channels: from gene to biological function. Cell Calcium, 2003. 33:519-531.
  3. Kheradpezhouh E, et al., TRPM2 channels mediate acetaminophen-induced liver damage. PNAS, 2014 111:3176-81