Inflammation has a significant impact on the drug metabolism

  • During certain diseases, such as influenza or cancer, pro-inflammatory proteins, so-called cytokines, are released from immune cells. These cytokines act as cell-to-cell communicators to activate the production of acute-phase proteins. These are proteins for the body’s defense, which are secreted by liver cells.

    At the same time, cytokines inhibit the break-down (metabolism) of drugs in the liver. This may lead to an accumulation of drugs, causing side effects in patients (see figure). The reason for this is not entirely clear, but it is assumed that liver cells shut down other processes in order to save energy for the acute phase response.

  • Using modern high-throughput technologies, the action of cytokines was studied in isolated human hepatocytes on a genome-wide level. Among several different types of the liver cells, human hepatocytes have a central role in the propagation and consecutive repression of an acute phase response in the liver. In this model it was confirmed that many genes encoding acute-phase response proteins were strongly induced. Genes encoding drug detoxification enzymes and transporters however, were strongly downregulated. The clinical situation was taken into account in the studies as well: liver tissues from patients with or without inflammation (using the C-reactive protein as a clinical diagnostic parameter) were analyzed. Together, this data characterize the extent of the human inflammation-response on gene regulation in a holistic, global context. Computer models have been constructed and used to understand and simulate the complex interactions that occur during this regulation of many liver-specific genes under inflammatory conditions.
  • Authors: Marcus Klein, Maria Thomas, Ulrich M. Zanger (Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart)

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