Detoxification Center and Greater Metabolic Organ: The liver assumes vital tasks in the body. Medications can damage the organ. These liver lesions are the most common cause of discontinuation of studies on drug candidates and market shutdown or adjustment of approved drugs. Although drugs have first been tested in many animal studies, it is difficult to correctly predict the risk of liver damage to humans in all cases. Human liver cell test systems in the culture dish (in vitro) could be an alternative to animal studies in the assessment of toxicological risks.
However, with the cellular systems developed so far, researchers can not always accurately determine whether a substance is toxic to humans or harmless to humans. Until now, only the culture dish can be measured, the concentrations of a substance damaging the cells. However, we would like to know how much a person can consume without toxic effects, or at what dose it becomes dangerous. An international team with the participation of the Leibniz Institute for Labor Research of TU Dortmund (IfADo) has developed a method that can be used to improve the performance of in vitro test systems.
Measurable indications for the optimization of the test system
In order to optimize the test systems, it is possible to turn with different adjustment screws. Because many parameters in the cell culture are recorded, for example, if important functions are disrupted, such as protein production. Until now, however, it has not been possible to reliably assess what parameters of cellular systems are best suited to map the situation in the body. In order to change this, appropriate measures are proposed in current research work: Using these mathematical methods, u.a. which of the many parameters allows the best distinction between hepatotoxic and non-toxic substances.
The researchers first examined 28 training substances using human liver cells grown in the laboratory. It was known whether or not the substance in question had hepatic toxicity in humans and at what dose there was a risk of liver injury. The new mathematical methods have provided information on the most reliable way of distinguishing toxic substances from non-toxic substances. "It became obvious, for example, that incubating the substance for 48 hours on the cells gave the best results and that only certain genes were helpful in its evaluation," says Wiebke Albrecht, author of the report. study and doctoral student at IfADo.
With this knowledge, the test system was optimized: all toxic substances for the liver were then correctly recognized. On the other hand, with two non-toxic substances, the system gave a false alarm. "After this phase of optimization, we have tested other substances, all of which have been properly classified, and to find out if the system really works, we have to look at more substances," says Albrecht.
Long-term goal: already toxic substances in cell culture at the prescribed therapeutic doses would be excluded from drug development and should therefore no longer be tested on animals.
The machine learning supports data processing
Using the test system, the researchers were also able to determine, for a substance they did not know, the amount of humans that could be absorbed daily without any identifiable health risk. A computer program was used to calculate the lowest toxic dose in cell culture, the dose taken orally in humans and the consumption in humans. The program examined how the human organism treats a substance.
"With our in vitro system, we have achieved similar levels of absorption, which are currently being achieved only on the basis of in-depth studies on animal nutrition," says Tim Brecklinghaus, author of the IfADo study. "However, we must study many more substances to understand the accuracy of the new method."
Forty-seven international researchers as well as representatives of federal and corporate authorities under the leadership of the Technical University of Dortmund and Ifado participated in the current publication. The study was published in the journal Archives of Toxicology. The research was funded by EU projects "EUToxRisk" and "TransQST", the European Regional Development Fund (CP16 / 00097) as well as various projects funded by the Federal Ministry of Education and Training. Research ("StemCellNet", "LiSyM", "LivSysTransfer" "," InnoSysTox "(also funded by the EU)).
Damage to liver of drug origin:
The term "drug-induced liver injury" refers to any liver injury caused by over-the-counter or prescription drugs. The spectrum ranges from mild and reversible damage to fatal damage. Until now, it is known that more than 1,000 drugs are potentially toxic to the organ. It is estimated that 1 to 10,000 to 100,000 people are affected each year. Drug-induced liver injury is the leading cause of acute liver failure in industrialized countries.
The Leibniz Institute for Labor Research of TU Dortmund (IfADo) – under the legal control of the Research Society in Occupational Physiology and Occupational Health and Safety eV – explores the potentials and risks of work modern science-based life and behavior. The results are used to establish the principles of performance and design of the world of work that promotes health. To this end, Ifado employs around 220 people. The institute is funded by institutional funds of the federal and state governments, as well as by third party funds (about 201 million euros in 2018). Ifado is a member of the association Leibniz, which brings together 95 independent institutions.
Mr. Sc. Wiebke Albrecht and Prof. Dr. med. Jan G. Hengstler
Department of Toxicology Research
Leibniz Institute for Work Research at TU Dortmund (IfADo)
Telephone: +49 231 1084-348
Albrecht, W., Kappenberg, F., Brecklinghaus, T. et al .: Prediction of human-induced hepatic injury (DILI) in relation to oral doses and blood concentration. Arch Toxicol (2019). doi: 10.1007 / s00204-019-02492-9 (Open Access)