The liver, which is a part of the gastrointestinal tract is the largest organ of the human body. Its function does not end at helping the digestion of food. It plays a key role in the homeostasis of the body. It participates in the metabolism of carbohydrates, fats and proteins, and also the synthetic processes take place in it, such as the coagulation factors. It is involved in the detoxification of chemicals, drugs and other xenobiotics, too. Due to variety of its functions is still exposed to damage. Although this organ has a large regenerative abilities, the possibilities of compensation in the course of acute liver failure are limited.
The most common causes of acute liver failure are damages caused by hepatotropic viruses and overdose of paracetamol (acetaminophen). It is a drug with analgetic activity and antipyretic effect, which patients willingly take, especially during autumn and winter, also because it is a substance being a part of many preparations available without a prescription. Unfortunately, just the small part of the population is aware of the side effects of paracetamol, considering it to be completely safe. In the case of a significant overshoot of the therapeutic dose it can lead to liver damage, heart muscle and kidney proximal tubular necrosis. The initial symptoms of the overdose such as nausea and vomiting, may be underestimated by patients. If it is followed by the sensitivity in the area of the liver or icterus, it usually announces the hepatic necrosis and life-threatening condition. It is worth mentioning that despite of the fact that the drug is rapidly absorbed, the adoption of high doses peak blood concentration is achieved even after 4 hours. There is an antidote to the substance N-acetylcysteine. However, it is often given too late, or it is not being able to stop a cascade of changes in hepatocytes. Therefore, in the most severe cases, the only currently known way to save the life of the patient is a liver transplant, which is not always possible in a timely manner, which can lead to death.
Paracetamol overdose causes many interrelated biochemical reactions in hepatocytes, including the formation of reactive oxygen, oxidation of protein responsible for the lipid peroxidation and DNA fragmentation. It is also known that, this pathology has to deal with an increase of intracellular calcium concentration. So far, research reports did not fully explain pathomechanisms of these changes. This theme was taken up by an Australian research team from the University of Adelaide. He stated that an overdose of paracetamol activates the TRPM2 channels (Transient Receptor Potential Melanostatine 2), which were previously known as those which participate in cell responses to stress and inflammation and the role in the development of insulin resistance. It has been proven that this cationic channel enables the calcium transport across the cell membrane, which in the case of the paracetamol overdose leads to the toxic concentrations of Ca 2 + in the cells, resulting in the death of hepatocytes. Researchers have demonstrated that the liver damage of mice, which had TRPM2 gene switched off, caused by acetaminophen was significantly lower in comparison to the wild type of mice. These figures demonstrate that the channel TRPM2 is essential in the mechanism of acetaminophen-induced hepatocyte death.
By understanding the role of TRPM2 channel in the development of acute liver failure in the course of an overdose of acetaminophen, we gained a new potential therapeutic target. In the future, we can use it to create a drug that will prevent the damage to the hepatocytes in this mechanism. We must remember that the liver does not only store and transform the drugs, but is also the subject of their toxic influence.
Written by: Aneta Szafraniec, Dominik Porada, Jerzy Bednarski
Source:
1. http://pl.wikipedia.org/wiki/Paracetamol
2. Rychkov GY, Barritt GJ, Expression and function of TRP channels in liver cells. Adv Exp Med Biol. 2011;704:667-86. doi: 10.1007/978-94-007-0265-3_35.
3. Kheradpezhouh E, Ma L, Morphett A, Barritt GJ, Rychkov GY., TRPM2 channels mediate acetaminophen-induced liver damage. Proc Natl Acad Sci U S A. 2014 Feb 25;111(8):3176-81. doi: 10.1073/pnas.1322657111. Epub 2014 Feb 3.
4. Zhang Z, Zhang W, Jung DY, Ko HJ, Lee Y, Friedline RH, Lee E, Jun J, Ma Z, Kim F, Tsitsilianos N, Chapman K, Morrison A, Cooper MP, Miller BA, Kim JK., TRPM2 Ca2+ channel regulates energy balance and glucose metabolism. Am J Physiol Endocrinol Metab. 2012 Apr 1;302(7):E807-16. doi: 10.1152/ajpendo.00239.2011. Epub 2012 Jan 24.
5. Gajewski P. (red.): Interna Szczeklika. Kraków: Wydawnictwo Medycyna Praktyczna, 2012, s. 1039-1041, 1077-1080, 2420-2421.
Would you like to know more? Watch on MEDtube.net:Examination Of The Liver
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The next step in the fight against paracetamol overdose
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