Induction and repression effects on CYP and transporter protein abundance by azole mixture uptake in rat liver

Authors

  • Helen Hammer NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany; SIGNATOPE GmbH, Reutlingen, Germany
  • Flavia Schmidt BfR, Department of Pesticides Safety, Max-Dohrn-Str. 8-10, 10589 Berlin, Germany
  • Tanja Heise BfR, Department of Pesticides Safety, Max-Dohrn-Str. 8-10, 10589 Berlin, Germany
  • Constanze Knebel BfR, Department of Pesticides Safety, Max-Dohrn-Str. 8-10, 10589 Berlin, Germany
  • Alexander Dabrowski BfR, Department of Pesticides Safety, Max-Dohrn-Str. 8-10, 10589 Berlin, Germany
  • Hannes Planatscher NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany; SIGNATOPE GmbH, Reutlingen, Germany
  • Carsten Kneuer BfR, Department of Pesticides Safety, Max-Dohrn-Str. 8-10, 10589 Berlin, Germany
  • Philip Marx-Stoelting BfR, Department of Pesticides Safety, Max-Dohrn-Str. 8-10, 10589 Berlin, Germany
  • Oliver Pötz NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany; SIGNATOPE GmbH, Reutlingen, Germany

DOI:

https://doi.org/10.17179/excli2020-2311

Keywords:

ABC transporter, azole fungicides, cytochrome P450, immunoaffinity-based mass spectrometry, liver toxicity, pesticides, pesticide mixtures, SLC transporter

Abstract

Detection of mixture effects is a major challenge in current experimental and regulatory toxicology. Robust markers are needed that are easy to quantify and responsive to chemical stressors in a broad dose range. Several hepatic enzymes and proteins related to drug metabolism like cytochrome-P-450 (CYP) enzymes and transporters have been shown to be responsive to pesticide active substances in a broad dose range and are therefore good candidates to be used as markers for mixture toxicity. Even though they can be well quantified at the mRNA level, quantification on the protein level is challenging because most of these proteins are membrane bound. Here we report the development of mass spectrometry-based assays using triple-x-proteomics (TXP) antibodies in combination with targeted selected ion monitoring (tSIM) to quantify changes of protein levels due to exposure to mixtures of pesticide active substances. Our results indicate that changes on the protein level of CYP1A1, ABCB2, ABCC3 are in line with observations on the mRNA and enzyme activity level and are indicative of mixture effects. Therefore, the tests are promising to reveal effects by chemical mixture effects in toxicological studies in rats.

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Published

2020-06-26

How to Cite

Hammer, H., Schmidt, F., Heise, T., Knebel, C., Dabrowski, A., Planatscher, H., … Pötz, O. (2020). Induction and repression effects on CYP and transporter protein abundance by azole mixture uptake in rat liver. EXCLI Journal, 19, 904–916. https://doi.org/10.17179/excli2020-2311

Issue

Vol. 19 (2020)

Section

Original articles

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Copyright (c) 2020 Helen Hammer, Flavia Schmidt, Tanja Heise, Constanze Knebel, Alexander Dabrowski, Hannes Planatscher, Carsten Kneuer, Philip Marx-Stoelting, Oliver Pötz

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