Investigation of the in vitro toxicological properties of the synthetic cannabimimetic drug CP-47,497-C8

• Published in: Toxicology and applied pharmacology Vol. 277; no. 2; pp. 164 - 171
• Main Authors: Koller, Verena J., Auwärter, Volker, Grummt, Tamara, Moosmann, Bjoern, Mišík, Miroslav, Knasmüller, Siegfried
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.06.2014; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; Biological and medical sciences; BONE MARROW; Cannabinoids - toxicity; Cell Membrane - drug effects; Cell Membrane - pathology; Cell Survival - drug effects; Comet Assay; CP-47,497-C8; Cyclohexanols - toxicity; Cytokinesis-block micronucleus (CBMN) cytome assay; Cytotoxicity; DNA; DNA Damage; DNA DAMAGES; Dose-Response Relationship, Drug; DOSES; Drug addictions; DRUGS; GENE MUTATIONS; Genes, Reporter; Genotoxicity; Hep G2 Cells; HORMONES; HUMAN POPULATIONS; Humans; IN VITRO; LIVER; Liver - drug effects; Liver - metabolism; Liver - pathology; LUCIFERASE; Medical sciences; MEMBRANES; Micronuclei, Chromosome-Defective - chemically induced; Micronucleus Tests; MICROSOMES; MIXTURES; Mouth Mucosa - drug effects; Mouth Mucosa - metabolism; Mouth Mucosa - pathology; Mutation; OXIDATION; Protein Biosynthesis - drug effects; RECEPTORS; Receptors, Estrogen - drug effects; Receptors, Estrogen - genetics; Receptors, Estrogen - metabolism; Risk Assessment; SALMONELLA; Salmonella typhimurium - drug effects; Salmonella typhimurium - genetics; SYNTHESIS; Synthetic cannabinoid; TOXICITY; Toxicology; Transfection; CP-47,497-C8; Cytotoxicity; Synthetic cannabinoid; Cytokinesis-block micronucleus (CBMN) cytome assay; Comet assay; Genotoxicity; Drug; Micronucleus test; Toxicity; CP-47.497-C8; Cannabinoid; In vitro; Synthetic product; DNA; Drug of abuse; Genotoxity test
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2014.03.014

Cannabicyclohexanol (CP-47,497-C8) is a representative of a group of cannabimimetic cyclohexylphenols which is added to herbal mixtures as a cannabis substitute since 2008. Although in the beginning CP-47,497-C8 was the main ingredient of “Spice” and similar products, it was partly replaced by aminoalkylindole-type cannabinoid receptor agonists like JWH-018, JWH-073 or JWH-250, but never completely disappeared from the market. Since information on its toxicological properties is scarce, we investigated the effects of the drug in human derived cell lines. The cytotoxic effects were studied in a panel of assays (SRB, XTT, LDHe and NR tests) in a buccal derived (TR146) and a liver derived (HepG2) cell line. The strongest effects were seen in the two former assays at levels ≥7.5μM indicating that the compound interferes with protein synthesis and causes membrane damage. In additional comet assays, DNA damage was detected at levels ≥10μM. Experiments with lesion specific enzymes showed that these effects are not due to oxidative damage of DNA bases. The negative findings obtained in Salmonella/microsome assays and the positive results of micronucleus tests with the cell lines indicate that the compound does not cause gene mutations but acts on the chromosomal level. In contrast to other synthetic cannabinoids, no indication for estrogenic/antiestrogenic properties was seen in a luciferase assay with bone marrow derived U2-OS cells. In conclusion, our findings show that the drug has only weak cytotoxic properties. However, the induction of chromosomal damage indicates that it may cause adverse effects in users due to its impact on the stability of the genetic material. •We tested the toxic properties of a synthetic cannabinoid.•Acute cytotoxic effects were detected with doses ≥7μM.•No hormonal effects were found.•DNA damage was detected at levels ≥10μM in comet assay and micronucleus tests.•Effects in directly exposed tissues may occur in humans.