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Archives of Toxicology

, Volume 87, Issue 7, pp 1287–1297 | Cite as

Toxicological profiles of selected synthetic cannabinoids showing high binding affinities to the cannabinoid receptor subtype CB1

  • Verena J. Koller
  • Gerhard J. Zlabinger
  • Volker Auwärter
  • Sabine Fuchs
  • Siegfried Knasmueller
Molecular Toxicology

Abstract

Products containing synthetic cannabinoids are consumed as a surrogate for marihuana due to their non-detectability with commonly used drug tests and their strong cannabimimetic effects. Because data concerning their toxicological properties are scarce, the cytotoxic, genotoxic, immunomodulatory, and hormonal activities of four naphthoylindole compounds (JWH-018, JWH-073, JWH-122 and JWH-210) and of one benzoylindole (AM-694) were studied in human cell lines and primary cells; tetrahydrocannabinol was included as the classical non-endogenous cannabinoid receptor ligand. All compounds induced damage to the cell membranes of buccal (TR146) and breast (MCF-7) derived cells at concentrations of ≥75–100 μM. No cytotoxic responses were seen in other assays which reflect mitochondrial damage, protein synthesis, and lysosomal activities. JWH-073 and JWH-122 induced DNA migration in buccal and liver cells (HepG2) in single cell gel electrophoresis assays, while JWH-210 was only in the latter cell line active. No estrogenic activities were detected in bone marrow cells (U2-OS), but all compounds caused anti-estrogenic effects at levels between 2.1 and 23.0 μM. Furthermore, no impact on cytokine release (i.e., on IL-10, IL-6, IL-12/23p40 and TNFα levels) was seen in LPS-stimulated human PBMCs, except with JWH-210 and JWH-122 which caused a decrease of TNFα and IL-12/23p40. All toxic effects were observed with concentrations higher than those expected in body fluids of users. Since genotoxic effects are in general linear over a wide concentration range and the exposure levels may be higher in epithelial cells or in serum, further experimental work is required to find out if DNA damage takes place in drug users.

Keywords

Spice Synthetic cannabinoid Cytotoxicity Genotoxicity Anti-estrogen Cytokine 

Abbreviations

LDHe

Extracellular lactate dehydrogenase

IL

Interleukin

NR

Neutral red

SRB

Sulforhodamine B

SCGE

Single cell gel electrophoresis

TNFα

Tumor necrosis factor α

XTT

2,3-Bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenyl-amino)carbonyl]-2H-tetrazolium hydroxide

Notes

Acknowledgments

This study was conducted in the frame of the project “Spice and synthetic cannabinoids” (JUST/2009/DPIP/AG/0948) and was financially supported by the EU Commission, the German Ministry of Health and the City of Frankfurt/Main. Furthermore, the authors are thankful to. P. Behnisch and H. Besselink (BioDetection Systems BV, The Netherlands) for their support in regard to the realization of the estrogen measurements.

Supplementary material

204_2013_1029_MOESM1_ESM.docx (44 kb)
Supplementary material 1 (DOCX 44 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Verena J. Koller
    • 1
  • Gerhard J. Zlabinger
    • 2
  • Volker Auwärter
    • 3
  • Sabine Fuchs
    • 4
  • Siegfried Knasmueller
    • 1
  1. 1.Department of Internal Medicine 1, Institute of Cancer ResearchMedical University of ViennaViennaAustria
  2. 2.Center of Pathophysiology, Infectiology and Immunology, Institute of ImmunologyMedical University of ViennaViennaAustria
  3. 3.Institute of Forensic MedicineUniversity Medical Center FreiburgFreiburgGermany
  4. 4.Christian Doppler-Laboratory for Molecular Biological Food AnalyticsUniversity of Veterinary MedicineViennaAustria

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