Tuesday, 18 August 2015 09:58

Organ-on-a-chip: New mechanism of paracetamol discovered Featured

An Israeli-German research team headed by Prof. Yaakov Nahmias from the Alexander Grass Center of Bioengineering at the Hebrew University in Jerusalem has developed an organ-on-a-chip model with a tiny human liver, which can be used longer than a month. Since they inserted additionally optoelectronic sensors into the cells, they were able to discover an important toxicity of acetaminophen.

The long-term toxicity of acetaminophen is mediated by the xenobiotic enzymes CYP2E1 and CYP3A4. The toxic metabolite N-acetyl-p- benzoquinonimin (NAPQI) causes protein adducts, which lead, among other things, to a damaging effect on the mitochondria impairing the cell respiration. In addition, an inflammatory response is initiated.

In the research, amongst others, the groups of Dr. Claus Duschl from the Fraunhofer Institute for Cell Therapy and Immunology in Potsdam, branch Bioanalysis and bioprocesses and Prof. Michael Schwarz from the Institute of Toxicology at the Tübingen University were involved. Both are present in the inVitro+Jobs Working Groups list.

The researchers cultivated tiny liver spheroids from human HepG2 / C3A or HeLa cells and used an integrated optical system in which the cells has been stained with a ruthenium dye. With a suitable excitation (532 nm) light, the cells respond with light emission, thereby oxygen served as a quencher of the fluorescence emission. By this real-time measurement of oxygen, the cellular respiration could be used as a marker for the condition of the cells.

With the help of this fine investigation methods, the researchers succeeded to detect smallest, very rapid changes in the cellular respiration. They measured that acetaminophen blocks the cell respiration much faster and at much lower doses as is generally assumed. Currently it is believed that the drug is primarily transformed into the toxic metabolites NAPQI and damages the cells after the transformation. Since the liver is able to deactivate NAPQI is is conventional assumed that only harms Acetaminophen only harms when it is taken in high doses or in the case of a liver disease.
With the new findings this was now being questioned.

Original Paper:
Sebastian Prill, Danny Bavli, Gahl Levy, Elishai Ezra, Elmar Schmälzlin, Magnus S. Jaeger, Michael Schwarz, Claus Duschl, Merav Cohen & Yaakov Nahmias (2015): Real-time monitoring of oxygen uptake in hepatic Bioreactor shows CYP450 independent mitochondrial toxicity of acetaminophen and amiodarone. Archives of Toxicology. DOI 10.1007 / s00204-015-1537-2. http://link.springer.com/article/10.1007%2Fs00204-015-1537-2