Detoxication Center and the largest metabolic organ: Jetra takes vital tasks in the body. Medications can damage the body. These liver injuries are the most common cause of abolition of drug candidate studies and abolition of approved drugs from the market or adaptation. Although drugs are first tested in numerous animal studies – it is difficult to predict the risk of liver damage to humans in all cases. Test systems from liver cells in a culture vessel (in vitro) may be an alternative to animal studies in assessing toxicological risk.
However, with so-developed cellular systems, researchers can not always determine whether the substance is toxic to humans or harmless to humans. So far, culture can only measure the concentration of substances that damage the cells. However, we would like to know how many people can consume without toxic effects, or in which doses it becomes dangerous. The international team with the participation of Leibniz Institute of Labor Research at TU Dortmund (IfADo) has now developed a method that can be used to improve the performance of in vitro test systems.
Measurable indications for test system optimization
In order to optimize the test systems, it is possible to rotate with different adjusting screws. Since numerous cell culture parameters have been noted, for example, whether important functions are disturbed, such as protein production. So far, it has not been possible to reliably estimate which parameters in cellular systems are best suited to mapping the body's condition. To make this change, appropriate measures are proposed in current research work: By using these mathematical methods, u.a. which by many parameters allow the best difference between hepatotoxic and non-toxic substances.
The researchers first examined 28 exercise substances using laboratory liver cell cultures. It was known whether a particular substance has liver toxicity to humans, and in which dose there is a risk of liver damage. New mathematical methods provided information on how to reliably distinguish between toxic and non-toxic substances. "It became obvious, for example, that incubating the substance for 48 hours on the cells yielded the best results and that only certain genes helped to evaluate," explains Wiebke Albrecht, the author of the study and the IfADo PhD.
With this knowledge, the test system is optimized: all toxic substances in the liver are properly recognized. On the other hand, with two non-toxic substances, the system gave a false alarm. "After this optimization phase, we have tested other substances, they are all properly classified. To find out how reliable a system really works, we need to examine more substances," says Albrecht.
Long-term goal: substances that are already toxic in cell culture at predicted therapeutic doses would be excluded from further drug development and therefore should no longer be tested on animals.
Machine learning supports data processing
In addition to the test system, researchers could also identify an unknown substance for them, which can absorb the number of people every day without recognizable health risks. The computer program helped calculate the lowest dose that is toxic in cell culture, oral dose in humans and human intake. The program has considered how the human body processes the substance.
"With our in vitro system we have reached similar levels of intake, which are currently being obtained only on the basis of detailed animal feeding studies," says author IfADo Tim Brecklinghaus. "However, we need to study many more substances to understand how new the method is correct."
This publication includes 47 international researchers as well as representatives of federal authorities and companies led by the Technical University in Dortmund and IfADo. The study was published in the journal Archives of Toxicology. The research was supported 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 Research ("StemCellNet", "LiSyM", "LivSysTransfer"). "," InnoSysTox "(also funded by the EU)).
Drug-induced liver damage:
The term "drug-induced liver damage" is compounded by all liver damage caused by prescription or prescription drugs. The spectrum ranges from mild to reversible to fatal damage. For now it is known that more than 1,000 drugs are potentially toxic to the body. It is estimated that one in 10,000 to 100,000 people per year are hit. Drug-induced liver damage is the leading cause of acute liver failure in industrialized countries.
Leibniz Institute for Labor Research at TU Dortmund (IfADo) – under the legal ownership of the Research Society for Occupational Physiology and Health and Safety at Work e.V. – explores the potentials and risks of contemporary work based on life and behavioral science. The results are used to carry out the principles of performance and healthy design of the world of design. For this purpose, IfADo employs about 220 people. The Institute is funded from the institutional funds of federal and state governments, as well as from third party financing (2018 a total of about 14 million euros). IfADo is a member of the Leibniz Association, which consists of 95 independent institutions.
Mr. Sc. Wiebke Albrecht and prof. Dr. Honey. Jan G. Hengstler
Research Department of Toxicology
Leibniz Institute for Labor Research at TU Dortmund (IfADo)
Phone: +49 231 1084-348
Albrecht, W., Kappenberg, F., Brecklinghaus, T. et al., Predicting Human Loss Disease (DILI) Disease Compared to Oral Doses and Blood Concentration. Arch Toxicol (2019). doi: 10.1007 / s00204-019-02492-9 (open access)