Archives of Toxicology

, Volume 90, Issue 6, pp 1369–1382 | Cite as

Impact of a synthetic cannabinoid (CP-47,497-C8) on protein expression in human cells: evidence for induction of inflammation and DNA damage

  • Andrea Bileck
  • Franziska Ferk
  • Halh Al-Serori
  • Verena J. Koller
  • Besnik Muqaku
  • Alexander Haslberger
  • Volker Auwärter
  • Christopher Gerner
  • Siegfried KnasmüllerEmail author
Molecular Toxicology


Synthetic cannabinoids (SCs) are marketed worldwide as legal surrogates for marihuana. In order to predict potential health effects in consumers and to elucidate the underlying mechanisms of action, we investigated the impact of a representative of the cyclohexylphenols, CP47,497-C8, which binds to both cannabinoid receptors, on protein expression patterns, genomic stability and on induction of inflammatory cytokines in human lymphocytes. After treatment of the cells with the drug, we found pronounced up-regulation of a variety of enzymes in nuclear extracts which are involved in lipid metabolism and inflammatory signaling; some of the identified proteins are also involved in the endogenous synthesis of endocannabinoids. The assumption that the drug causes inflammation is further supported by results obtained in additional experiments with cytosols of LPS-stimulated lymphocytes which showed that the SC induces pro-inflammatory cytokines (IL12p40 and IL-6) as well as TNF-α. Furthermore, the proteome analyses revealed that the drug causes down-regulation of proteins which are involved in DNA repair. This observation provides an explanation for the formation of comets which was seen in single-cell gel electrophoresis assays and for the induction of micronuclei (which reflect structural and numerical chromosomal aberrations) by the drug. These effects were seen in experiments with human lymphocytes which were conducted under identical conditions as the proteome analysis. Taken together, the present findings indicate that the drug (and possibly other structurally related SCs) may cause DNA damage and inflammation in directly exposed cells of consumers.


Synthetic cannabinoid Comet assay Lymphocytes Proteomics 





Bovine serum albumin


Cannabinoid receptors






False discovery rate


Gas chromatography–mass spectrometry


Proton nuclear magnetic resonance


Liquid chromatography–mass spectrometry


Label-free quantification




Nuclear buds


Nuclear division indices


Nucleoplasmatic bridges


Polyacrylamide gel electrophoresis


Peripheral blood mononuclear cells




Synthetic cannabinoids


Single-cell gel electrophoresis


Sodium dodecyl sulfate





This study was funded by the EU Commission in the frame of the coordinated Project “SPICE and synthetic cannabinoids” (JUST/2009/DPIP/AG/0948).

Compliance with ethical standards

Conflict of interest

The authors state that they have no conflict of interest.

Supplementary material

204_2015_1569_MOESM1_ESM.docx (11 kb)
Supplementary material 1 (DOCX 11 kb)
204_2015_1569_MOESM2_ESM.docx (90 kb)
Supplementary material 2 (DOCX 90 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Andrea Bileck
    • 1
  • Franziska Ferk
    • 2
  • Halh Al-Serori
    • 2
  • Verena J. Koller
    • 2
  • Besnik Muqaku
    • 1
  • Alexander Haslberger
    • 3
  • Volker Auwärter
    • 4
  • Christopher Gerner
    • 1
  • Siegfried Knasmüller
    • 2
    Email author
  1. 1.Faculty of Chemistry, Institute of Analytical ChemistryUniversity of ViennaViennaAustria
  2. 2.Department of Internal Medicine 1, Comprehensive Cancer Center, Institute of Cancer ResearchMedical University of ViennaViennaAustria
  3. 3.Department of Nutritional SciencesUniversity of ViennaViennaAustria
  4. 4.Institute of Forensic MedicineUniversity Medical Center FreiburgFreiburgGermany

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