TRPM2 channels mediate acetaminophen-induced liver damage

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 Ca 2+ homeostasis, covalent modification and oxidation of proteins, lipid peroxidation, and DNA fragmentation. Although an increase in intracellular Ca 2+ 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 Ca 2+ rise. Here we report that the channel responsible for Ca 2+ 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 H 2 O 2 or the intracellular application of ADP ribose. siRNA-mediated knockdown of TRPM2 in hepatocytes inhibits activation of the current by either acetaminophen or H 2 O 2 . In TRPM2 knockout mice, acetaminophen-induced liver damage, assessed by the blood concentration of liver enzymes and liver histology, is significantly diminished compared with wildtype mice. The presented data strongly suggest that TRPM2 channels are essential in the mechanism of acetaminophen-induced hepatocellular death.

Role of CYP2E1 in Mitochondrial Dysfunction and Hepatic Injury by Alcohol and Non-Alcoholic Substances

“…As mentioned earlier, in addition to nitroxidative PTMs of many mitochondrial proteins, oxidation of lipids (lipid peroxidation) would also result in the production of potently cytotoxic lipid peroxides such as 4-HNE, MDA, 4-oxonon-2-enal (4-ONE), and acrolein (ACR), as reported with chronic alcohol drinking and/or smoking, HFD, or APAP [208, 226–228]. Lipid peroxidation can produce protein adducts with many amino acids such as Cys, His, and Lys [229, 230].…”

Circadian Clock Regulation of Hepatic Lipid Metabolism by Modulation of m6A mRNA Methylation

“…At 10–14 weeks of age, 10 male mice per group were sacrificed via CO 2 asphyxiation at Zeitgeber Time (ZT) 0,2,6,10,12,14,18,22. In order to induce high levels of ROS in the liver, WT male mice were fasted 12 h and followed by intraperitoneal injection with 300 mg/kg APAP dissolved in PBS and re-fed (Kheradpezhouh et al, 2014; Mossanen and Tacke, 2015). Mice were sacrificed at 6 h after APAP injection.…”

Renoprotection: focus on TRPV1, TRPV4, TRPC6 and TRPM2

“…were able to demonstrate that curcumin, the natural occurring polyphenol in turmeric spice, inhibits ADPr‐induced TRPM2 currents providing at least in part a model for the hepatoprotective properties of curcumin (Kheradpezhouh et al . , ). Another approach to develop specific TRPM2 blockers was taken by Shimizu et al .…”